It is currently Sun Oct 22, 2017 1:52 pm



All times are UTC - 5 hours [ DST ]


Our Sponsors





Post new topic Reply to topic  [ 26 posts ]  Go to page 1, 2  Next
Author Message
PostPosted: Sun Nov 21, 2010 5:02 pm 
Ok so im in my 18th month of treatment. I started May 7, 2009. Everything was great for roughly 12 to 13 months. Well, let me say this first. I did have one problem thoughout the beginning but its gotten 100% better. I had problems peeing while standing. Now, like i said that problem is gone and i can pee just find standing up but for some reason i feel like i have too pee 24/7. Within 5 minutes after peeing i already feel the urge to go again. I've told all this to my doctor and he said that all the symptoms i explained to him sounded like prostate problems. However, he said prostate problems at my age(25) was not likely and he sent me on my way. I've been tested for all and every STD and its not that thank god. Im safe in that relm of things anyways. One of the weirder things about the whole thing is, it only bothers me if im sitting or laying down. As long as im up and moving around its not really that bad but just as soon as i sit or lay down it bothers me tremendously. I will speak of one thing that seemed to help me. I started out at 24mgs a day. Well once i started having this problem i was so miserably fed up with it that i figured i would decrease my dose a bit to see if that helped. I dropped from 24mg's to 16mg's. Crazy enough it actually got better. So, i've been at 16mg's for a bit now but the problem has come back. I didnt really have any problems with decreasing from 24mg's to 16mg's but im fearful of dropping any lower. I guess their really isnt any one specific question here except for maybe if someone has ever experienced this or could offer advice i would be greatful. I know i've been taking the medication for long enough that i probably could go a bit lower on my dosage but like i said, im fearful of doing so. I've seen where people say they didnt really experience any withdrawal symptoms until around 2mg's but i am so scared of withdrawal. Its a thing of my past and its one reason i chose this route of treatment. Aside from the fact that i've tried rehab after rehab with horrible outcomes. I know that eventually if and when i decide to stop the medication their will be withdrawal. That i do know but im definitely not wanting to discontinue the medication yet. I just feel that i probably need to lower my dosage and im very scared to do so. Im so stable at 16mg's and i really dont wanna throw myself off but its looking like i dont have a choice. Unless i can figure out why im having this peeing problem. I cant imagine why the medication would cause this problem but like i said, when i decreased my dose it got better. Oh its soooo aggravating!! Any ideas or suggestions would be great. Thanks!! ~PEACE~


Top
  
 
 Post subject:
PostPosted: Sun Nov 21, 2010 5:30 pm 
Offline
Long Time Member
Long Time Member
User avatar

Joined: Wed Apr 29, 2009 12:55 pm
Posts: 4847
Location: Leesburg, FL
I can totally empathize with you about having peeing problems. I have a bladder condition and have a sacral nerve stimulator - it's the only thing that makes me pee like a normal person. So I know how much that kind of problem can interfere with your daily life. With that said, if your doctor is poo-poo'ing you and your issues, I'd ask to see a urologist. What you are describing is not normal and any urological problem should at least be ruled out. I know some men have said that suboxone affects their urination, but I'd rule out any physiological cause before you just accept it and decide to tolerate it. Your age may make you less likely to have problems, but it doesn't make it impossible. Good luck. :)

_________________
-As I have grown older, I've learned that pleasing everyone is impossible, but pissing everyone off is a piece of cake.

-I'm only responsible for what I say, not for what you understand.


Top
 Profile  
 
 Post subject:
PostPosted: Sun Nov 21, 2010 6:07 pm 
Offline
Super Poster
Super Poster

Joined: Mon Sep 20, 2010 10:09 am
Posts: 104
I have to agree w/Hatmaker. Just because you SHOULDN'T have a prostate problem, or any problem for that matter, doesn't mean you don't have something going on. That comment made your dr. sound ignorant. With that said, dealing w/major constipation, I drink a ton of water. I may use the bathroom a few times a day, but as soon as lie down to sleep, I end up waking up almost every hour on the hour to pee A LOT. If I drink what a "normal" person would, I'm fine throughout the night. I do find it odd that when I do drink, I have to go mostly at night. And when I go, it's like I drank a case of beer each time. Use to happen to me on methadone too. An hour after getting dosed I'd have to go so bad, then again 30 minutes later. I know there aren't any answers here, but wanted to let you know you're not alone. I do want to make sure you understand that it only happens to me if I drink a lot of water. Like a gallon. I don't drink much else but some O.J. or milk. No alcohol. Oh, and I'm 34.


Top
 Profile  
 
Our Sponsors
 Post subject:
PostPosted: Sun Nov 21, 2010 7:39 pm 
Wow thanks for the replies!! I will try to address everything i can remember in yalls replies. Please forgive my memory it is horrible. I definitely am gonna set up an appointment with a urologist. I went to my regular doctor for a check up this past monday and got blood work done, my heart checked etc. Basically a head to toe check up. I go in tomorrow for a follow up and to get a stress echo done. In active addiction i not only used opiates, i was into a lot of other stuff as well. Ecstasy, cocaine etc. I have really done some damage to my body especially my heart. You mentioned constipation. Every morning i wake up at 5a.m. I walk my dog, come in and take my medication at about 5:30. At about 7:30 i eat a bowl of grits with some chocolate donuts. I know, weird combo but i love it lol. Anyways, after my breakfast i have to drink 2 glasses of water all at once in order to make it easy to use the bathroom. I dont wanna say its easy but the water really does help tremendously. I usually pee all that water out within a 2hour time period. I have to do this every day or else im constipated and very uncomfortable all day. Anyways, i know drinking water like that may have something to do with my peeing problem but i dont believe its the sole reason for it. After tomorrow if all my bloodwork and test come back good then im gonna make an appointment with a urologist. I been praying about it. Thanks again for everyones reply!! I'll let everyone know what i come up with. Thanks!! ~PEACE~


Top
  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 10:35 am 
Constipation can give you a false urge to pee because the colon can get distended and press on the bladder.


Top
  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 11:59 am 
Yea that sounds about right. I havent ever thought about that. Although most the time im not constipated. Once i use the bathroom each morning im good to go until the next morning. Only sometimes am i constipated an its the most uncomfortable feeling ever. I can feel the pressure all day long until the next day and no matter how much water i drink it just wont cooperate. Anyways, enough about that subject lol. I went today and got a stress echo done and according to the "cardiologist" my heart is fine other than im in really bad shape. He made me so angry cuz after the test and him saying that nothing was wrong, he basically treated me like i had waisted his time. Im not gonna let him bother me though because i would much rather get the test done and him say nothing was wrong than to not get the test and their be something wrong. Well, so far all the test i've had done have came back fine so i guess im gonna have to find a urologist. I cannot imagine what the problem is. Well, wish me luck!! ~PEACE~


Top
  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 3:51 pm 
Offline
Long Time Member
Long Time Member
User avatar

Joined: Thu Oct 21, 2010 10:39 am
Posts: 4026
Location: Sitting at my computer
While on Suboxone I urinated frequently as well. Waking several times during the night to go pee was frustrating. I drank from 3 to 4 cups of coffee a day and figured that was part of the problem. Went to see my Dr. and to my HORROR, he wanted to do a prostate exam...UGH! Anything but the finger up the wazoo, but I figured I better man up and do it, never had it done before. Turns out my prostate was inflamed causing insufficient emptying of the bladder? You know the box of tissues they give you after the exam...I thought they were for wiping the tears from my eyes. Turns out your supposed to wipe a lot lower than where your eyes are located...hell I didn't know!

Anyways, cutting out the coffee helped a lot. Emptying my bladder properly (which may take a minute or two) helped a lot too. The Dr. did say something about some med for the prostate inflammation, but I decided not to go the 'pill' route on this one. I have had a couple of 'follow ups' since this most embarassing procedure and all is well down below AND I know what the tissues are for now!


Top
 Profile  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 5:50 pm 
Thanks for your help Romeo!! I cant help but laugh about the whole tissue thing lol. As far as the other, that sounds like a strong possibility. I may need too get that test done, unfortunately. Im 25. If you dont mind me asking, how old are you? Im asking because im just curious if at my age that same thing is possible. You know, you may actually be onto something. In the middle of the night i usually only pee once or twice and im talking about i pee a lot each of those times. Concluding that by me peeing a lot im fully emptying my bladder and peeing much less. I've read that buprenorphine can affect the prostate. I wander if thats whats happening. I dont drink coffee anymore. I only drink water. Do you by chance know if their is something you can take or maybe even a non-medicinal remedy that could reduce the inflammation if that were the case? Another reason i think that may be my problem is, it really only bothers me while im sitting or laying down. I would be relieved in a way to know thats what it is because not knowing is horrible and makes me worry about it. Well, thanks again for the help!! Everyone has given me some great info!! ~PEACE~


Top
  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 6:20 pm 
Offline
Long Time Member
Long Time Member
User avatar

Joined: Fri Mar 12, 2010 12:43 am
Posts: 1017
Location: Buffalo New York
I hope I can help you. I also ran into this problem 2 and half years into my sub treatment. But in a sense I had a nervous breakdown from that day on I felt like I had to pee nonstop to the point where I didn’t sleep for 5 straight days and ended up in the psych ward to get sleeping meds cause the ER will only give out xannax and ambien but the Doctors in the psych ward deal with mental health so I was give the strongest sleeping pill prescribed and that help me sleep but still had the pee problem. So I got into a urologist had all the test done took different bladder meds which help but didn’t make a huge difference. So things got so bad I went through the worst pain I’ve ever felt in my life and had a cystoscopy that’s where they stick shift up your pee hole ouch. All to find out that nothing was wrong. So one day I had a flare up after having intercourse and told my urologist about this and he told that he thinks it might be mental health do to I have obsessive compulsive disorder and after he said that it made sense. Cause your mind is such a powerful thing and all you can think about when this is happening is why is this happening to me oh my god I just want to be able to relax and you have it in your head that suboxone is doing this to me which I also did the same thing. But there is a good chance that this could be a mental health issue. Once I was put on Prozac to help with my obsessive thoughts things got a thousand times better I still have the occasional bad day were I fell like I got to pee part of the day but no were close to as bad b4 I was put on Prozac KNOCK ON WOOD!

SO my advice to you is rule out all physical health issues and if nothing pops up then talk with a therapist about this issue.


Top
 Profile  
 
   
 Post subject:
PostPosted: Mon Nov 22, 2010 6:29 pm 
Offline
Long Time Member
Long Time Member
User avatar

Joined: Thu Oct 21, 2010 10:39 am
Posts: 4026
Location: Sitting at my computer
I'm glad you found the tissue story amusing...I DIDN'T, it took a box of tissues to dry up my tears after that ordeal. :shock: I felt like he was the ventriloquist and I was the poor dummy he was trying to get to speak! :D Just kidding. Understandably, I find this forum lacks humor at times, so I interject some when I can.

I just turned 43. I believe I was 41 when I lost my anal virginity.

I believe Saw Palmetto is a natural/homepathic way to reduce prostate inflammation. You better google it and check before stocking up on it though.

Try concentrating on emptying your bladder fully for a while then maybe try cutting down on your fluids for maybe a day or two and see how the urination goes.

Good luck and keep us posted on your results. I'm sure there are others out there who would benefit from knowing your results.


Top
 Profile  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 7:22 pm 
Thanks again Romeo and i will definitely try some of those techniques and keep everyone updated. Bboy, you have no idea how many times i sit here saying, please lord i just wanna be able to sit here, relax and enjoy myself but im never able to do so. I would also have to agree that their are times where i do believe its psychological. I've had the problem for quite awhile now so its become an obsession for sure but i absolutely cannot help it. Most the time its all i can think about because its so annoying and uncomfortable and its every second of every day. The only time i get relief and this also makes me think its somewhat psychological is when im asleep at night. Once i get to sleep at night i usually only wake up once maybe twice every night depending on what time i go to sleep. I wake up, pee like a freakin race horse and back to sleep i go and very comfortable. Not like during the day. The daytime is horrible!! Its like hell on earth. I probably pee 15 to 20 times a day. But its never really a lot. I think instead of peeing all at once, its taking what should be 1 good bathroom trip and spreading it out in little bits throughout the whole entire freakin day. Ugghh its so aggravating!! Another thing you mentioned, when you said it flared up. Thats what seems to happen for me. Not that exact way but meaning their are times when its fine but then times when it is exactly as you said, a flare up. Im just gonna make an appointment with a urologist an go from their. But in the meantime im gonna do some of those things Romeo mentioned. Cut back on fluids etc. I will keep you all updated. Thanks again everyone for all the helpful advice!! This site is a true miracle!! ~PEACE~


Top
  
 
 Post subject:
PostPosted: Mon Nov 22, 2010 10:46 pm 
Offline
Long Time Member
Long Time Member
User avatar

Joined: Fri Mar 12, 2010 12:43 am
Posts: 1017
Location: Buffalo New York
lifesaver wrote:
Thanks again Romeo and i will definitely try some of those techniques and keep everyone updated. Bboy, you have no idea how many times i sit here saying, please lord i just wanna be able to sit here, relax and enjoy myself but im never able to do so. I would also have to agree that their are times where i do believe its psychological. I've had the problem for quite awhile now so its become an obsession for sure but i absolutely cannot help it. Most the time its all i can think about because its so annoying and uncomfortable and its every second of every day. The only time i get relief and this also makes me think its somewhat psychological is when im asleep at night. Once i get to sleep at night i usually only wake up once maybe twice every night depending on what time i go to sleep. I wake up, pee like a freakin race horse and back to sleep i go and very comfortable. Not like during the day. The daytime is horrible!! Its like hell on earth. I probably pee 15 to 20 times a day. But its never really a lot. I think instead of peeing all at once, its taking what should be 1 good bathroom trip and spreading it out in little bits throughout the whole entire freakin day. Ugghh its so aggravating!! Another thing you mentioned, when you said it flared up. Thats what seems to happen for me. Not that exact way but meaning their are times when its fine but then times when it is exactly as you said, a flare up. Im just gonna make an appointment with a urologist an go from their. But in the meantime im gonna do some of those things Romeo mentioned. Cut back on fluids etc. I will keep you all updated. Thanks again everyone for all the helpful advice!! This site is a true miracle!! ~PEACE~


Yea man I was in the same place where it just got to the point were I’m on my knees praying god just let me be able to relax for a little bit. Cause like you said it’s on your mind all day every day and no matter what you do it doesn’t go away. And it gets to the point where it affects your social life as in going on out, or work school everything ya know. And flares up I don’t just have it that way even now after it was figured out I still have flare ups some days. For ex I have panic attack issues and if I have a really bad panic attack ill have the pee problem for the next couple days.

Do you have any stress issues??? Because these 2 things go hand and hand for me when I’m stressed to this date ever since this started I get the urgency to go to the bathroom.


Things that have worked for me is working out just cardio, keeping as busy as possible and like you said what works great for me is holding it for a lil bit and stretching out when you go to the bathroom. I realized the more urine I get out at one time the less pressure I had on my bladder for longer times. But if I only get a lil out like you I feel like I have to go again in a couple minutes. And I know ill get shit for this but I don’t know if you are a male or not but ever since I started sitting down when I went to the bathroom since this started the more I can get out then standing.

Like I said your best bet is to rule out all normal bladder issues and go from there if nothing pops up then it might be something you want to look into with a psychologist!


Top
 Profile  
 
 Post subject:
PostPosted: Fri Jun 24, 2011 4:54 pm 
Offline
Power Poster
Power Poster
User avatar

Joined: Tue May 24, 2011 8:43 pm
Posts: 66
Location: Detroit, Michigan
I know this thread is old but here is why you, or anyone else reading this, are peeing so much.

κ-Opioid receptor ligands are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH).[14]

It's the Kappa opiods fault :P


Top
 Profile  
 
   
PostPosted: Fri Aug 15, 2014 4:00 am 
Offline
New Poster
New Poster

Joined: Fri Aug 15, 2014 3:26 am
Posts: 1
I am brand new to this forum. I realize this thread is outdated, but the OP has described down to a T what I've been going through lately. I started on Suboxone in April 2013 to get away from Opana and get my life back in order. I moved into a halfway house a week after starting the treatment. I had a decent job driving a forklift, got in shape with the Insanity program, ect. Anyway I had no issues with frequent urination until late last year. I was checked for STDs, urinary infections, and nothing was wrong. My mother talked me into getting off the subs, and suggested I make a radical change and move up to NYC. My sister is a model up there and does catering on the side. My mother wanted me to move on with my life and try something new. I was reluctant to go, because my life was finally back on track. I didn't want to screw up again. I've been to rehab before, stayed clean for four months, got out on my own, and started using again. Anyway, she finally talked me into it. I was taking 12mg a day at the time, called and cancelled my appt., and tried to wean myself off with what I had left. Well I went through minor withdraw for a couple days, and I caved. I was ashamed for taking drugs again and attempted to hide it. I went to NYC sick, decided to come back andstart over. The peeing problem had faded away when I stopped subs. I've been back on subs for about three months now, 4mg a day, and the frequent urination issue has been hell the past month or so. I don't notice it if I am up and moving, but if I'm laying around or trying to sleep it's awful. I will sit on the toilet for an hour straight it seems, trying to fully empty my bladder. It does no good. I don't want to offend any ladies in here, but if I'm laying down and it starts up, I can grab my member and it seems to subside(not for sexual pleasure). Anyway, I decided I really want to get off the Subs, get back to my old self, and have my natural energy again. 25 years old. So two weeks ago, I cut myself off again. The physical withdraws were almost non existant. The mental however, made me think I had no energy, and I started to crave again. I absolutely wouldn't let myself go back to drugs again though. I had called my family, friends, and anyone I could possibly buy drugs from to tell them I was trying to quit subs, and not to let me buy anything I shouldn't. Just in case. Well I made it 7 days without subs, and the urination issue vanished. I got scared however, thought I may need to wean down lower than 4mg and start my workout program again to build up strength before trying to quit. I been back on subs for about a week now. The urgency to urinate while lying down is driving me nuts. I think stopping subs will be the only way to end this for good. I apologize for the gigantic story. If anyone has a solution for the constant urge to urinate, or a decent solution for the mental withdraws when I quit, I'm all ears. Thank you


Top
 Profile  
 
PostPosted: Fri Jan 13, 2017 3:55 am 
Offline
Average Poster
Average Poster

Joined: Fri Jan 13, 2017 3:26 am
Posts: 4
I know this is old but I see new replies and have the exact same problems. I too did not experience them until about 6-8 months use. For me it is both. The constant urge to urinate and the inability to urinate which becomes crippling to the point that I can no longer bathe or barely leave the house. I did the Urologist thing and all the tests except a uroscopy, in fear of the pain and my Uro's insistence that he wouldn't do it under any anesthesia as the pain is not bad. Well I knew that lie and it is often done under Valium IV sedation. Anyway my other tests were all normal and he said unless I wanted to do the uroscopy it must be the Subutex. Mind you I started on Suboxone and developed horrible side effects from the naloxone and had to switch. The urinary issues were and are debilitating. So after the tests I brought it up to my Sub doc and he got angry stating that it's not possible and not from the Sub. I jumped the next day from 8mg. For the first 4-5 the urge to pee got worse but I was able to go now without problems and I went a lot. By day 6-7 the urinating problems ceased but for me this is when withdrawal really set in and by day 10 I was back to the Subs. I've tried cutting my dose, skipping days, switching brands and all helped but either temporarily or not enough. I believe that it is bcs of the opiate receptors in your urinary tract. With Bupe being so much stronger than other opiates than so is its metabolite norbuprenorphine which goes through the urinary system. I also believe in the mental aspect making it worse. I am to the point where I am deathly afraid it will be permanent and I will one day need a catheter. So I am on day 3 of a 6mg drop. The PAWS I can get through it's when the Bupe is completely out of my system that I get true opiate w/d. Has anyone had this problem and actually quit Bupe and did it get better permanently?


Top
 Profile  
 
PostPosted: Fri Jan 13, 2017 5:58 pm 
Offline
Moderator
Moderator
User avatar

Joined: Thu Feb 23, 2012 4:42 am
Posts: 4255
I'm searching for articles regarding buprenorphine and urination urgency and/or overactive bladder and I'm finding very little. In fact the research I'm seeing indicates that opioids can be used to help treat overactive bladder/urination urgency.

I'll keep looking.

Amy

_________________
Done is better than perfect!


Top
 Profile  
 
PostPosted: Fri Jan 13, 2017 6:39 pm 
Offline
Moderator
Moderator
User avatar

Joined: Thu Feb 23, 2012 4:42 am
Posts: 4255
OK, here's an article that seems to suggest that naloxone can have an antagonizing effect on bladder irritation in rats. The article is fairly complicated unless medical research articles are your thing.

The point of the article was that the gene therapy that they were trying by transmitting genes to spinal nerves via a replication-defective herpes simplex virus worked in calming significant bladder pain and irritation, even when the targeted afferent nerves were antagonized by naloxone.

Any other articles I've found suggest that opioids seem to have the opposite effect than what you are experiencing.

Article:
Gene Therapy for Bladder Overactivity and Nociception with Herpes Simplex Virus Vectors Expressing Preproenkephalin
Hitoshi Yokoyama,1,* Katsumi Sasaki,1,* Michael E. Franks,1 William F. Goins,2 James R. Goss,2 William C. de Groat,3 Joseph C. Glorioso,2 Michael B. Chancellor,4 and Naoki Yoshimuracorresponding author1,,3
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a major challenge to treat. We studied the effect of targeted and localized expression of enkephalin in afferent nerves that innervate the bladder by gene transfer using replication-defective herpes simplex virus (HSV) vectors in a rat model of bladder hyperactivity and pain. Replication-deficient HSV vectors encoding preproenkephalin, which is a precursor for Met- and Leu-enkephalin, or control vector encoding the lacZ reporter gene, were injected into the bladder wall of female rats. After viral vector injection, quantitative polymerase chain reaction showed high preproenkephalin transgene levels in bladder and dorsal root ganglia innervating the bladder in enkephalin vector-treated animals. Functionally, enkephalin vector-treated animals showed reductions in bladder hyperactivity and nociceptive behavior induced by intravesical application of capsaicin; however, vector-mediated expression of enkephalin did not alter normal voiding. This antinociceptive effect of enkephalin gene therapy was antagonized by naloxone hydrochloride administration. Together, our results with HSV vectors encoding preproenkephalin demonstrated physiological improvement in visceral pain induced by bladder irritation. Thus, gene therapy may represent a potentially useful treatment modality for bladder hypersensitive disorders such as IC/PBS.

Go to:
Introduction
interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder pain disease with unknown etiology. The incidence of IC/PBS varies greatly, ranging from 2 to 200 in 100,000, and the number of symptomatic patients is projected to be as high as 5000 per 100,000. While bladder pain is the hallmark feature of IC/PBS, proposed treatments, both medical and surgical, have had limited clinical utility in this debilitating disease (Payne et al., 2007).

One mechanism by which bladder pain is induced is postulated to involve chronic tissue inflammation that can lead to functional changes in C-fiber afferents (Yoshimura and Birder, 2007). Hyperactivity and emergence of mechanosensitivity of C-fiber afferents may lead to pain sensation in response to normal nonnoxious distension of the bladder. Histochemical analysis of bladders from patients with IC/PBS revealed marked edema, vasodilation, proliferation of nerve fibers, and infiltration of mast cells (Johansson et al., 1997; Theoharides et al., 2001) that have also been observed in chemically induced cystitis in animals, in which increased urinary frequency is initiated by sensitizing mechanosensitive afferents and/or recruitment of afferents normally unresponsive to mechanical stimulation (Häbler et al., 1990; Sengupta and Gebhart, 1994; Dmitrieva and McMahon, 1996; Dmitrieva et al., 1997; Yoshimura and Birder, 2007).

It has been well documented that enkephalinergic mechanisms in the brain and spinal cord have inhibitory effects on the micturition reflex, and that exogenous enkephalins or opiate drugs applied to the sacral spinal cord can depress micturition (Dray and Metsch, 1984; Hisamitsu and de Groat, 1984; Booth et al., 1985; Dray et al., 1985; de Groat et al., 1986a, 1993). Endogenous enkephalins are expressed in bladder afferent and efferent pathways to inhibit micturition (Glazer and Basbaum, 1980; de Groat et al., 1986b; de Groat, 1987). Preproenkephalin (PPE) A is one of three genes that encode endogenous opioid peptides. Its main product, enkephalin, is synthesized in a variety of central and peripheral neurons. PPE gene knockout mice demonstrate an altered response to painful stimuli in the formalin test, which supports the role of endogenous opioids, such as enkephalins, in nociceptive processing (Konig et al., 1996). In patients with IC/PBS, frequent or unremitting pain may also require pain management with long-acting opioids such as morphine (MS Contin, Oramorph) or oxycodone (OxyContin) (Erickson, 1999; Ratner, 2001). However, the use of systemic opioid therapy has been limited because of its untoward side effects, tolerance, and dependency (Foley, 1993; Way, 1993). Thus, there remains an unmet need to deliver therapeutic peptides to the bladder afferents in a manner that releases biologically relevant levels of the opioids, which block chronic pain, without the unwanted side effects or tolerance attributed to the current drug therapies.

Herpes simplex virus type 1 (HSV-1) represents a viral vector system with several biological features that make it attractive for gene delivery to the peripheral or visceral nervous system (Fink and Glorioso, 1997; Wilson et al., 1999; Fink et al., 2000). Replication-defective mutants have been created that are deleted for specific viral immediate-early (IE) genes that abrogate the ability of the virus to replicate but enable these vectors to rapidly establish a “latent-like” state within neurons and other cell types with which the virus comes in contact. The potential utility of HSV gene therapy for treating peripheral nervous system (PNS) disease in vivo has been shown by expression of a number of genes to date (Antunes Bras et al., 1998; Wilson et al., 1999; Braz et al., 2001; Goins et al., 2001; Goss et al., 2001, 2002a,b; Yamada et al., 2001; Chattopadhyay et al., 2002a,b; Hao et al., 2003, 2005; Liu et al., 2004; Sasaki et al., 2004; Yeomans et al., 2004, 2006; Meunier et al., 2005; Wolfe et al., 2007; Yang et al., 2008).

The present study examines whether targeted and localized expression of enkephalin in afferent nerves, which innervate the bladder, using HSV vector-based gene transfer, can reduce bladder pain and urinary frequency induced by chemical bladder irritation. We used a replication-defective HSV-1 vector, SHPE (Goss et al., 2001), engineered to carry the human PPE (hPPE) transgene to the bladder and its sensory nerves. Our current results demonstrate the presence of the vector in both the bladder and dorsal root ganglia (DRG; sixth lumbar [L6] and first sacral [S1]), using quantitative polymerase chain reaction (qPCR), and successful vector-mediated transgene expression in the bladder as well as its afferent pathways originating from L6 and S1 DRG as measured by histochemical staining and real-time (RT)-PCR. Physiologically, inhibitory enkephalinergic effects on bladder hyperactivity in urethane-anesthetized rats treated with intravesical capsaicin, as well as capsaicin-induced bladder nociceptive behavior in freely moving, unanesthetized rats, were shown after bladder inoculation with SHPE, but not the lacZ-expressing SHZ control vector.

Go to:
Materials and Methods
Vectors

The SHPE vector was created by the introduction of a plasmid that contained the human cytomegalovirus (CMV) promoter/enhancer, simian virus 40 (SV40) intron, human PPE cDNA, and SV40 poly(A) sequence with a loxP site into the thymidine kinase locus of a replication-defective vector deleted for the ICP4 immediate-early gene (Goins et al., 2001; Goss et al., 2001). The Escherichia coli lacZ gene was introduced into an ICP4– replication-defective virus in a similar fashion to create the recombinant virus SHZ, which was used as a control virus (Mester et al., 1995). Viral stocks were prepared with the E5 cell line (Deluca et al., 1985) in 10-layer Nunc Cell Factories (Thermo Fisher Scientific, Waltham, MA) at a multiplicity of infection (MOI) of 0.01, and purified by tangential flow filtration and ion-exchange chromatography as previously described (Ozuer et al., 2002a,b; Wechuck et al., 2002; Jiang et al., 2004). Titers for both SHPE and SHZ were determined in triplicate on E5 cells according to standard protocols (Goins et al., 2002).

Viral infection

All experiments were performed on female Sprague-Dawley rats (250–300 mg; Hilltop Animal Care, Pittsburgh, PA) in accordance with the requirements and recommendations in the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research, 1985) approved by the University of Pittsburgh (Pittsburgh, PA) Institutional Animal Care and Use Committee (IACUC). Under isoflurane anesthesia, a low midline incision was performed to expose the bladder and 20 μl of viral suspension (total, 5.0 × 108 plaque-forming units [PFU]) of SHPE or SHZ was injected at four different sites (5 μl at each point) on the bladder wall, using a 30-gauge Hamilton syringe. In the study in which nociceptive behavior and bladder capacity were simultaneously recorded, 20 μl of viral suspension (low-titer group, 7.0 × 107 PFU; high-titer group, 8.7 × 108 PFU) was injected into the bladder wall in the same manner.

Histochemistry

One week after bladder injection with the SHZ control vector, animals were killed and bladders and DRG were harvested. Cryostat sections (10 μm) of bladder and DRG were mounted on gelatin-coated slides and the slides were fixed for 1 min in 1.5% glutaraldehyde (Sigma-Aldrich, St. Louis, MO), rinsed twice in phosphate-buffered saline, and incubated overnight at 37°C in β-galactosidase substrate [0.4 mg/ml 5-bromo-chloro-3-indolyl-β-d-thiogalactopyranoside (X-Gal; Roche, Indianapolis, IN), 1 mM MgCl2, 5 mM K4Fe(CN)6, and 5 mM K3Fe(CN)6 in phosphate-buffered saline]. After several washes in phosphate-buffered saline, sections were counterstained with eosin.

Viral genome and transgene quantitation in target tissues

Seven, 14, and 30 days postinjection, bladder tissue and L6 and S1 DRG from rats injected with SHPE (n = 3) or SHZ were removed and snap-frozen at –80°C. DNA was isolated with a QIAamp DNA mini kit (Qiagen, Valencia, CA). We quantified the viral genome number per 800 ng of total tissue DNA with a GeneAmp 5700 real-time PCR sequence detection system (Applied Biosystems, Foster City, CA). We used Primer Express software (Applied Biosystems) to design the forward (5′-ATTTGGGAAACCTGCAAGGA-3′) and reverse (5′-GGGTGCTGGTGCCATCTT-3′) primers, as well as the TaqMan fluorogenic probe (5′-TCCTGCAGCTGTCCAAACCAGAGCT-3′, with 6-FAM at the 5′ end and TAMRA at the 3′ end), specific to the human PPE sequence. We amplified tissue DNA samples for 50 cycles (95°C for 15 sec/60°C for 60 sec) and this was quantified by comparison with a standard curve representing a known amount of virus. All samples were run in triplicate. At various times postinjection of SHPE, RT-PCR amplification with a radioactive probe specific to the human PPE cDNA sequence produced DNA products that were separated on a 1.2% agarose gel and stained with ethidium bromide. Negative controls included SHZ-injected animals.

Cystometrograms

One week after intramural bladder injection of either SHPE or SHZ, animals were given subcutaneous urethane anesthesia (1.14 g/kg). With a lower midline abdominal incision, we exposed the bladder and inserted PE-50 tubing through the dome and into the bladder. Saline was then infused transvesically at 0.04 ml/min; rats voided spontaneously per urethra. A software package (WinDaq; DATAQ Instruments, Akron, OH) was used for data collection and data manipulation.

After a baseline was established with saline infusion, we infused capsaicin (15 μM in 10% ethanol 10% Tween 80, and 80% saline) into the bladder at 0.04 ml/min to acutely promote bladder hyperactivity in SHPE (n = 10) and SHZ (n = 9) rats. After establishing bladder hyperactivity, we administered (SHPE, n = 7; SHZ, n = 6) opioid receptor antagonists to delineate an opioid effect of this response to intravesical capsaicin. First, we gave naloxone methiodide (Sigma-Aldrich), which does not pass through the blood–brain barrier (BBB), at 5 mg/kg body weight, intravenously. One hour after naloxone methiodide administration, we gave rats naloxone hydrochloride (Sigma-Aldrich), which passes through the BBB, at 5 mg/kg body weight, intravenously.

Simultaneous evaluation of nociceptive behavior and bladder capacity

In previous studies (Craft et al., 1993; Saitoh et al., 2008), intravesical instillation of resiniferatoxin, a capsaicin analog, induced two types of nociceptive behavior: abdominal licking (licking) and immobility with pointing of their nose toward the lower abdomen without licking (freezing). In this study, therefore, these two nociceptive behaviors were counted to evaluate bladder pain induced by intravesical application of capsaicin. The methods for simultaneous recordings of nociceptive behavior and voided volume in freely moving, uncatheterized rats followed those described in another study (Saitoh et al., 2008). In brief, 2 weeks after bladder injection with SHPE (n = 6) or SHZ (n = 6), rats were placed in metabolic cages for at least 1 hr for acclimation. Rats were then placed in a Bollman-type restraining device (KN-326; Natsume Seisakusho, Tokyo, Japan). A polyethylene tube (PE-50; Clay Adams Division of Becton Dickinson, Parsippany, NJ ) was inserted into the bladder through the urethra, and residual urine was withdrawn. Capsaicin (1 mM) was then instilled into the bladder via the catheter in a volume of 0.6 ml and kept there for 1 min. Thereafter, the transurethral catheter was removed and rats were placed back in the metabolic cage. Licking and freezing were scored by a blinded observer for 15 min that was divided into 5-sec intervals. When licking or freezing occurred during each 5-sec interval, it was scored as one positive event. Simultaneously, micturition patterns were recorded for 75 min and the average voided volume was defined as the total urine volume divided by the number of micturitions.

Statistics

The nonparametric Mann–Whitney U test was used to test for differences between SHPE and SHZ intercontraction intervals in cystometry, sensory ganglial PPE transgene levels, nociceptive behavior, and voided volume in a metabolic cage study. Parametric analyses were done within groups (SHPE and SHZ) after specific treatments (capsaicin, naloxone) in cystometry.

Go to:
Results
Initial experiments were designed to address the ability of replication-defective HSV vectors to deliver and express transgene in the bladder and bladder afferent nerves after injection of the vector into the bladder wall. These first experiments exploited the SHZ vector, as this control vector readily expresses the E. coli lacZ transgene (Mester et al., 1995) instead of the PPE gene. After injection of the vector into four sites within the bladder wall, we observed histochemical activity for β-galactosidase in both the bladder and L6 DRG 7 days after intramural bladder injection of SHZ. No staining was visualized in the L4 sensory ganglia, or in saline-injected controls (data not shown). Bladder wall sections displayed transgene expression predominantly within the smooth muscle cell layer at 1 week (Fig. 1A). L6 and S1 DRG sections demonstrated staining of small- and medium-sized cell bodies (Fig. 1B). No expression was detected in larger cell bodies (denoted by asterisks in Fig. 1B).

FIG. 1.
FIG. 1.
β-Galactosidase staining in rat bladder and L6 DRG after SHZ vector injection into the bladder wall. (A) A section of X-Gal-stained/eosin-counterstained SHZ-injected rat bladder (original magnification, ×10), with β-galactosidase ...
We had shown that a vector (SHZ) expressing a reporter gene injected into the bladder resulted in transgene expression in both bladder and DRG neurons after bladder wall vector injection. Next, we examined expression of the therapeutic product in target tissues. We studied SHPE vector-mediated expression of the transgene in various tissues by RT-PCR, using primers specific for the human PPE cDNA (Fig. 2) that fail to hybridize to the endogenous rat PPE sequence. The 70-bp hPPE product of the amplification was found (Fig. 2, arrow) to be present in RNA isolated from the bladder and L6 and S1 DRG of rats 1 week after SHPE injection, whereas SHZ-injected animals showed no amplification product from bladder samples (Fig. 2) or any DRG (data not shown), supporting expression of the therapeutic gene in the target tissues by SHPE but not the SHZ control vector.

FIG. 2.
FIG. 2.
RT-PCR analysis of HSV SHPE vector-mediated human preproenkephalin (hPPE) gene expression in bladder and DRG. Gel electrophoresis of PCR amplification products was performed with primers specific for the human preproenkephalin sequence. Amplification ...
We also wanted to correlate hPPE expression with the presence of HSV vector. Therefore we examined the number of viral genomes in bladder and DRG tissue 7, 14, and 30 days after bladder injection, using quantitative real-time PCR (Fig. 3). At all time points, mean bladder viral vector genome numbers were greater than the number of vector genomes present in DRG samples (Fig. 3A). A significant difference was demonstrated, between viral genomes/800 ng of DNA from L4 DRG and L6 DRG, at 7 days (0.5 ± 0.2 and 6.97 ± 1.43, p < 0.05), 14 days (0.03 ± 0.02 and 4.75 ± 1.55, p < 0.05), and 30 days (0.68 ± 0.25 and 11.4 ± 4.33, p < 0.05) (Fig. 3B). This result is consistent with L6 innervation of the bladder in rats. Vector genomes were also higher in S1 DRG than in L4 DRG, which does not contain bladder afferent neurons; however, the differences were not statistically significant at any of the three time points examined.

FIG. 3.
FIG. 3.
Quantitative PCR analysis for the presence of HSV vector genomes in SHPE-injected rat bladder and L4, L6, and S1 DRG tissues. (A) The number of viral vector genomes present in the bladder was 1–2 logs higher than in DRG. (B) The number of vector ...
Now that we had demonstrated the presence of viral vector genomes and therapeutic gene expression in the bladder and bladder afferent pathways, we designed assays to evaluate the therapeutic effect of PPE expression on bladder responses to nociceptive stimuli, using two methodologies (cystometry and metabolic cage measurements). In the first series of experiments, we performed cystometries on urethane-anesthetized rats 1 week after bladder inoculation with either SHPE or SHZ, as shown by the cystometrograms (CMG) for SHPE- and SHZ-injected rats depicted in Fig. 4. During saline infusion, no significant differences in intercontraction intervals (ICIs) were observed between the two groups (Fig. 5). Thereafter, when 15 μM capsaicin was continuously infused into the bladder after a baseline was established with saline, both SHPE- and SHZ-injected rats showed bladder hyperactivity as evidenced by significant reductions in ICI (36.9 and 61.3% decrease, respectively). However, the reduction of ICI in the SHPE-injected rats was significantly smaller than that obtained with the SHZ control vector-injected rats (ICI, 10.4 ± 2.8 vs. 6.8 ± 2.3 min after capsaicin, respectively; p < 0.01) (Fig. 5A).

FIG. 4.
FIG. 4.
Representative example of in vivo continuous cystometrograms (CMGs) of urethane-anesthetized rats, with CMG performed 1 week after mural injection of SHPE (A) or SHZ (B). The SHPE-treated rat showed a smaller reduction in intercontraction interval (ICI) ...
FIG. 5.
FIG. 5.
Intercontraction intervals (ICIs) in urethane-anesthetized rats injected 1 week previously with SHPE or SHZ. (A) Both SHPE- and SHZ-treated rats showed a reduction in ICI after capsaicin treatment; however, this reduction was significantly smaller in ...
While continuing capsaicin infusion, rats were treated with two types of naloxone to establish whether the antinociceptive effect on capsaicin-induced bladder hyperactivity in SHPE-injected rats was opioid dependent (Figs. 4 and ​and5).5). Administration of naloxone hydrochloride (Nal H) significantly antagonized the antinociceptive effect of SHPE vector-mediated expression of hPPE, which is cleaved to Met- and Leu-enkephalin (10.4 ± 2.8 min before naloxone hydrochloride to 5.4 ± 1.7 min after naloxone hydrochloride; p < 0.01); however, naloxone methiodide (Nal M) did not antagonize the antinociceptive effect (10.4 ± 2.8 min before naloxone methiodide to 9.8 ± 3.5 min after naloxone methiodide) (Fig. 5B). No change was seen in the SHZ-injected rats after administration of either naloxone (6.8 ± 2.3 min before naloxones to 6.8 ± 1.6 min after naloxone methiodide, and to 5.8 ± 1.6 min after naloxone hydrochloride), consistent with the inability of the control vector to produce factors that alter bladder hyperactivity induced by nociceptive stimuli (Fig. 5B).

In addition to performing cystometric studies on anesthetized rats treated with the enkephalin vector and in which bladder hyperactivity was induced with capsaicin, we also employed metabolic cage studies to further assess the effect of SHPE vector treatment on nociceptive behavior and bladder function in freely moving, unanesthetized rats. In addition, to evaluate behavior and bladder activity in the uncatheterized condition, we used a brief application (1 min) of capsaicin at a concentration of 1 mM, which was higher than the concentration (15 μM) used for continuous infusion (1–2 hr) in cystometry. We also evaluated the effects of SHPE treatment 2 weeks after the bladder injection in order to examine whether the effects of hPPE gene transfer last more than 1 week, as consistent with HSV vector-mediated transgene expression that lasted up to 4 weeks (Goins et al., 2001; Sasaki et al., 2004). We have found that the number of freezing events during a 15-min period after intravesical capsaicin was significantly reduced in SHPE-injected rats compared with SHZ-injected rats, by 64% in the low-titer group (40.2 ± 9.0 vs. 14.4 ± 4.9, respectively; p < 0.05) and 68% in the high-titer group (37.0 ± 9.6 vs. 11.7 ± 3.0, respectively; p < 0.05) (Fig. 6B). However, there was no significant difference in capsaicin-induced licking behavior between SHZ- and SHPE-injected rats (low-titer group, 23.0 ± 6.4 vs. 16.8 ± 3.0; high-titer group, 20.1 ± 4.8 vs. 20.0 ± 6.8, respectively) (Fig. 6A). In addition, the average voided volume during the 75-min interval after intravesical instillation of capsaicin was significantly larger in SHPE-injected rats compared with SHZ-treated rats in the high-titer group (0.84 vs. 0.46 ml, respectively; p < 0.05) (Fig. 6C). In the low-titer group, bladder capacity tended to increase in SHPE-injected rats compared with SHZ-injected rats (0.88 vs. 0.67 ml, respectively), but was not significantly different (Fig. 6C).

FIG. 6.
FIG. 6.
HSV vector-mediated hPPE effects on nociceptive behavior and bladder capacity after intravesical instillation of capsaicin. The scores for licking (A) and freezing (B) behaviors were counted as one positive event when it occurred during a 5-sec interval, ...
Go to:
Discussion
Endogenous enkephalins have been identified by immunohistochemical techniques in sensory afferent terminals in the brain and spinal cord (Glazer and Basbaum, 1980; de Groat et al., 1986b; de Groat, 1987), and are thought to colocalize with excitatory neurotransmitters, such as substance P, in the nociceptive pathway at the spinal cord level (de Groat et al., 1986b; de Groat, 1987). Data from Yoshimura and North (1983) and Mudge and colleagues (1979) support both the direct inhibitory effect of opiates on sensory nerve conduction and neurotransmitter release in vitro. Yaksh and associates (1980) also demonstrated reduced substance P release in spinal cord neurons after administration of intrathecal morphine in anesthetized rats. Exogenous administration of enkephalin or opiate drugs produced a reduction in the micturition reflexes in rats and cats (Dray and Metsch, 1984; Hisamitsu and de Groat, 1984; Dray et al., 1985; de Groat et al., 1986a), as well as antinociceptive effects in a behavioral rat model (Craft et al., 1995). More recently, studies have demonstrated that the DNA for PPE, the precursor to the enkephalin class of opioid peptides, can be successfully transferred into DRG cells via their peripheral terminal fields, using HSV vectors (Goss et al., 2001, 2002b; Hao et al., 2003), with antinociceptive results that can be blocked by intrathecal naloxone administration. In all instances vector-mediated enkephalin expression induced a block in the natural nociceptive response that was transient whether examined in the chronic formalin test, the bone cancer model, or even the spinal nerve ligation (SNL) model. Moreover, successful readministration of the vector led to an even more vigorous response compared with the initial vector injection. However, it still remained transient in nature, dissipating between 14 and 21 days postinjection. Together, these data suggest, given the successful transduction of the target tissue and possible physiologic relevance, that gene therapy with hPPE may be useful in the treatment of bladder-hypersensitive disorders such as IC/PBS.

In this study we have demonstrated successful delivery of the hPPE cDNA by replication-defective HSV vectors in the bladder afferent pathways of rats. Because it is known that enkephalins and other opioid drugs applied in the sacral spinal cord depress bladder activities (Dray and Metsch, 1984; Hisamitsu and de Groat, 1984; Booth et al., 1985; Dray et al., 1985; de Groat et al., 1986a, 1993), it seems reasonable to assume that after PPE gene therapy, enkephalin expressed at central terminals of bladder afferent nerves in the spinal cord could directly exert inhibitory effects on spinal neurons involved in the micturition reflex and bladder nociceptive sensation. The concept that HSV vector-based gene therapy with PPE has an antinociceptive effect, regardless of etiology, is novel and may have important clinical implications as other current drug therapies have not proven effective in the entire patient population with IC/PBS.

Because of the difficulty in demonstrating enkephalinergic immunohistochemical staining, as reported by others (de Groat et al., 1986b; Pohl et al., 1994), we chose to evaluate marker gene (lacZ) transfer in the rat bladder and DRG tissue. The selective staining in small- and medium-sized cell bodies of the L6 DRG may reflect specific uptake of the virus in bladder afferents known to be of this size (Yoshimura and Birder, 2007), which has been previously noted for wild-type HSV infection of mouse footpad, where peripheral inoculation of virus resulted in the presence of virus in small- and medium-sized C-fibers and Aδ-fibers but not the larger myelinated Aβ-fibers (Yang et al., 2000; Margolis et al., 2007).

Results of both RT-PCR for the human enkephalin gene and quantitative PCR for vector genomes complement the previously described histochemical findings. PPE transgene levels in the bladder and L6 DRG were consistent with uptake by afferent nerves of either viral particles or PPE after synthesized by the vector in the bladder where there were 1–2 logs greater viral genomes in the bladder compared with DRG. Thus, the presence of vector-mediated enkephalins in L6 and S1 DRG may be due to transcription of the human PPE gene cassette from viral genomes present within DRG neurons or the result of expression in the bladder and retrograde transport of the peptides to the bladder afferent nerves, or both. Our current assays cannot rule out either mechanism. Interestingly, injection of SHPE into the bladder demonstrated a trend of increased PPE transgene levels in L6 more than S1 DRG tissue (Fig. 2), consistent with prior reports that bladder innervation is found to be more numerous in L6 DRG than in S1 DRG in rats (Keast and de Groat, 1992; Su et al., 1997). Sustained transgene levels at 1 month were observed in both bladder and L6 DRG; however, the strongest levels were observed from 7 to 14 days postinjection. The CMV promoter used to drive hPPE in the background of SHPE is known to maintain expression during this period of time, as shown by Wilson and colleagues (1999). However, we have also detected expression from this promoter after 14 days; the levels have been reduced as expression still seems to be transient from this promoter (Goins et al., 2001; Goss et al., 2001, 2002a; Sasaki et al., 2004). The issue of duration of expression needs to be explored further, and the mechanism of promoter shutoff, in the background of the replication-defective HSV vector, needs to be better defined.

In this study, cystometric analyses showed a physiologic antinociceptive effect due to PPE gene transfer. Another important point is that although bladder hyperactivity was altered, normal voiding did not appear to be affected by viral infection or expression of the hPPE therapeutic gene, consistent with the findings of Wilson and colleagues (1999) in the peripheral nervous system; this suggests that baseline sensation remains intact with hPPE gene transfer. Furthermore, the augmented response to intravesical capsaicin in SHPE-injected rats was antagonized by naloxone hydrochloride, but not by naloxone methiodide, which is a quaternary salt opioid receptor antagonist that does not pass the blood–brain barrier (BBB), suggesting that HSV-mediated enkephalin gene transfer exerts its effects in the central nervous system rather than in the periphery. It is possible, but unlikely, that the reduced ICI we observed could be due to the effects of naloxone hydrochloride at the supraspinal level, because the differential response in control (SHZ) and SHPE-treated rats given intravesical capsaicin as an acute bladder irritant suggests that the effect was opioid mediated in SHPE rats, probably because of HSV vector-mediated enkephalin expression in afferent nerves. Thus, it seems reasonable to assume that HSV vector-mediated enkephalin gene therapy suppressed bladder irritation induced by capsaicin via activation of naloxone-sensitive opioid receptors in the spinal cord.

Last, we further assessed the effect of SHPE vector treatment on nociceptive behavior and bladder function in freely moving, unanesthetized rats, situations that more closely mimic IC/PBS in human patients, and found that nociceptive freezing behavior induced by intravesical application of capsaicin was significantly reduced in SHPE-injected rats compared with SHZ-injected rats. At the same time, voided volume that was evaluated simultaneously with nociceptive behavior was significantly increased in SHPE-injected rats compared with SHZ-injected rats. However, there was no difference in capsaicin-induced licking behavior between SHZ- and SHPE-injected rats. This is probably due to the fact that licking behavior is induced by stimulation of urethral afferents in the pudendal nerve rather than bladder afferents, because previous studies by us and others have demonstrated that pudendal nerve transection significantly reduces licking behavior induced by intravesical application of capsaicin (Lecci et al., 1994) or resiniferatoxin (Saitoh et al., 2008). This also provides evidence that the effects of PPE gene transfer after SHPE bladder inoculation are limited to bladder afferent pathways and neither the vector nor the transgene is having pleiotropic effects on other nontarget sites.

In conclusion, this study demonstrated proof of concept for the use of gene therapy to treat visceral pain. The results of the present study indicate that (1) HSV vectors injected into the bladder wall were transported through bladder afferent pathways to L6 and S1 DRG, where bladder afferent nerves originate, and these viral genomes expressed human PPE; (2) bladder hyperactivity induced by nociceptive stimuli (i.e., capsaicin) can be reduced via naloxone-dependent opioid mechanisms, presumably at the spinal cord level, after SHPE bladder inoculation; and (3) nociceptive freezing behavior induced by intravesical capsaicin was also suppressed in association with increased bladder capacity after SHPE but not SHZ control vector treatment. Our data illustrate that enkephalin gene therapy for bladder pain response is not only feasible but achieves a physiological decrease in bladder irritative response. This technique of gene transfer using replication-defective HSV vectors may offer new hope for the treatment of refractory IC/PBS. However, because this study used only an acute bladder irritation model and HSV injection before bladder pain induction, further studies using chronic bladder irritation models and postirritation injection paradigms of HSV vectors are necessary.
End Article.

Amy

_________________
Done is better than perfect!


Top
 Profile  
 
PostPosted: Tue Jan 24, 2017 2:09 am 
Offline
Average Poster
Average Poster

Joined: Fri Jan 13, 2017 3:26 am
Posts: 4
Amy, thank you so much for all the effort and time spent on this old thread. Just an update. Today is day 15 since the initial drop from 6-8 to nothing. As suspected the problem got worse in urgency but better in ability. Everything seemed to improve. Until day 12. The withdrawal is not so bad anymore but all of a sudden the problem is back. As with you, I have not found many scientific articles on the matter but have seen much discussion about it on numerous boards. I did contact the original maker of Subutex n Suboxone, after a lengthy dance the woman said they did have a Dept. devoted solely to scouring the internet lookinng for discussions about problems with their products. She did transfer me and although hasty, the man stated "Yes this is a problem that we have seen and know about but there are not enough cases yet to officially declare it a side effect. Then I spoke with the FDA, they said basically the same thing so I filled out a report. The only temporary relief that I have found for this is Phenazopyridine HCL. But this too is not a fix as long term use is highly warned against. I'm just wondering why it disappeared and came back so suddenly. Thanks again.


Top
 Profile  
 
PostPosted: Tue Jan 24, 2017 10:45 am 
Offline
Power Poster
Power Poster
User avatar

Joined: Fri Feb 26, 2016 12:20 pm
Posts: 44
Location: Toledo, OH
Anyone reading this now (as I know this post is VERY old) just wanted to share something I went through...

I always try to drink a lot of water, being that I have hyperhidrosis and sweat A LOT (subs makes it worse) and also have chronic Migraines so I am always trying to stay hydrated, well last summer I was going pee seriously EVERY 5 MINS, and it wasn't just a little bit (like a UTI), it was like my bladder was FULL, EVERY SINGLE TIME I went. and it got to be worrying (and VERY annoying) so I went to my family dr, she wanted to test my pee for a UTI even though I KNEW that wasn't it, because I have had uti's in the past and was NOTHING like this, no pain at all, just peeing VERY frequently, and A LOT.

Well she did a quick urine sample and said there was small traces of blood in my urine. I guessed it could be from NSAID's because at the time I was taking them practically every day for my head and in the past I had stomach problems from them so I figured that was the cause..

My DR made me see a urologist, he made me measure every single time I peed, for like 4 days straight, and keep records of how much I peed every single time. (I also had to keep record of everything I drank, and how many OZ each time) needless to say that was a pain. bringing a big plastic toilet thing to work and having to measure my urine all day.... BUT when I went back in for a check up, they told me I was drinking over 3X what you should normally drink in a day and that I drink too much water. SERIOUSLY??? I have a bad sweating problem (not to mention this happened in summer) AND with my migraines I cant get dehydrated or it triggers them badly, so I thought this was RIDICULOUS they were telling me I drink too much, especially water.

They still wanted to do more tests, and even a SURGERY (all because my dr said there were tiny traces of blood in my urine... which could be from anything... I'm on like 5 different medications and I believe it is possible for that to be a cause, even though I was sure it was the NSAID's) . I had to do an ultrasound, CT, and have a cystoscopy..

The cystoscopy was pure hell. even though I was put under, and they did it as an outpatient surgery, I was peeing PURE BLOOD for 2 weeks!!! AND it felt like RAZOR BLADES, my urethra was bleeding for days and I would seriously cry every time I had to pee, it hurt SO FUCKING BAD! & I never cry, so that showed how painful it was.

After they were done with the cystoscopy the urologist told my boyfriend that everything looked fine, I just had extra blood vessels in my bladder or some stupid shit. So after thousands of dollars in pointless medical bills they tell me I DRINK TOO MUCH LIQUIDS. I wanted to kill somebody. To NOT drink enough liquids with my medical issues is purely STUPID. SO now I try to space out my drinking, and not drink too much before bed. and I haven't had the issue since all this. even though its not 90 degrees out anymore, but u get the idea...

Idk if the weather was just super hot and humid (my apartment doesn't have central A/C and with hyperhidrosis I am ALWAYS super hot and sweaty, even in winter) and I was drinking a lot to make up for how much I had been sweating, or what, but I was so mad I had to go through all this crap and all this money to find out I just drink more than most people........ Needless to say I was very annoyed.

So if anyone is still reading this and really think something is wrong (like I did), I urge you to get it checked out. it could be nothing serious (like me) or it could be something. But u will never know unless you see a Dr. BUT I cant stress how much I was peeing, and how often. and it all turned out to be that I just drink a lot... so whoever is reading this for advice I would say just get yourself checked out. rather be safe than sorry! and good luck

_________________
"Though no one can go back and make a brand new start, Anyone can start from now and make a brand new ending." -Unknown


Top
 Profile  
 
PostPosted: Tue Jan 24, 2017 5:57 pm 
Offline
Average Poster
Average Poster

Joined: Fri Jan 13, 2017 3:26 am
Posts: 4
Thank you. Also, thank you for verifying my fears of having a cystoscopy. Well it's a day latrer and things are ok again. I've limited my fluids a bit and am not embarrassed to admit that male kegal(?), exercises, seem to help also. I truly believe that it is the drug, how it acts on different Kappa receptors and how all this messes up our Mictruition process. Also, as all feelings of pain, cold/hot sensitivity and such are super heightened during a detox maybe it's a waiting game. Never had blood in urine but your explanation makes tons of sense. This is a long process so to others, hang in there. And to those who respond, thank you.


Top
 Profile  
 
Display posts from previous:  Sort by  
Post new topic Reply to topic  [ 26 posts ]  Go to page 1, 2  Next

All times are UTC - 5 hours [ DST ]


Who is online

Users browsing this forum: rule62 and 0 guests


You cannot post new topics in this forum
You cannot reply to topics in this forum
You cannot edit your posts in this forum
You cannot delete your posts in this forum
You cannot post attachments in this forum

Search for:
Jump to:  
Our Sponsors
Suboxone Forum latest topics RSS feed Subscribe to the entire forum
 

 

 
Fond Du Lac Psychiatry
Dr. Jeffrey Junig, M.D., Ph.D.

  • Board Certified Psychiatrist
  • Asst Clinical Professor, Medical College of Wisconsin

Powered by phpBB® Forum Software © phpBB Group