BERKELEY, CA (UroToday.com) - The previous research of our workgroup had focused on microbiota, inflammation, and oxidative stress. While that work dealt with the links between microbiota, inflammation and oxidative stress, I felt that I should address the pain pathogenesis as well. The question is what exactly is the cause of pain, and how does oxidative stress fit into the picture?
The key puzzle pieces of the hypothesiswere as follows:
- some prostatitis patients have oxidative stress and pain without overt inflammation
- signs of heat and cold sensitization have been found in prostatitis patients
- pain can cause oxidative stress via neuronal mitochondria (animal studies)
- spinal oxidative stress is implicated in pain (animal studies)
- primary sensory afferents can sense spinal oxidative stress through pain receptors on the terminus of spinal process
- NSAIDs and fluoroquinolones have displayed effects comparable to placebo
- antioxidants and tetracycline have displayed effects superior to placebo
Therefore, if it is plausible that pain causes spinal oxidative stress, then it is plausible that spinal oxidative stress contributes to sensitization primary sensory afferents towards further stimuli (it is as if backwards signaling to primary sensory afferents in this case) and contributes to systemic oxidative stress as well (that may contribute to risk of other diseases).
The most relevant limitation of the hypothesis is that on the one hand, peripherally measurable oxidative stress is not a plausible case of pain (as exemplified by asymptomatic inflammatory prostatitis), while in the other hand, spinal oxidative stress is a plausible cause of pain.[3,4] Therefore, peripheral oxidative stress is probably not the root component of ongoing prostatitis.
Some aspects of the hypothesis are based on animal rather than human studies. In addition, it has been only described that isoprostanes are released from nervous tissue but the mechanism of isoprostanes’ passive or active release from neurons has not been described to the best of my knowledge.
Another important limitation is that peripheral sensitization mechanisms may be higly relevant. Prostatitis patients have an increased level of nerve growth factor in their seminal plasma. Some patients may have a leaky urothelium that is sensitive to potassium ions. Even if there is no overt inflammation, then it is still possible that there is a covert inflammation in obstructed prostatic ducts, to name a few pathogenetic mechanisms suggested. Therefore, spinal sensitization does not exclude peripheral mechanisms at all.
Finally, the strongest clinical evidence argues in favor of using alpha-blockers for the treatment of prostatitis, and those drugs have a peripheral action. Without a lengthier discussion, it certainly suggests the relevance of peripheral mechanisms.
There is a saying - before looking for right answers look for the right questions. I aim to do my best as follows:
- According to a controlled study, prostatitis syndrome patients are effectively treatable with tetracycline. While the effect thereof can naturally be attributed to antibiotic effect, it still raises a question - why did tetracycline perform so much better than fluoroquinolones? Is it purely due to sensitivity of putative causative organisms, or also due to other effects of tetracyclin like antioxidant properties or anti-calcification effects?
- Why are prostatitis patients’ right anterior insulae altered? Is that a sign of supraspinal sensitization connected to spinal sensitization, or something different?
- What is the relevance of central sensitization when compared to peripheral sensitization in prostatitis patients? Is it possible that the pain could be effectively reduced by existing molecules or their functional analogues capable of blocking nociceptive pain?
- Free-radical mediated pathways generate electrophilic lipid peroxidation products. Some lipids yield pro-inflammatory, others yield anti-inflammatory compounds, depending on lipid type. If omega-3 derived electrophilic compounds are anti-inflammatory, could prostatitis syndrome patients benefit from omega-3 supplementation?
- Türk S, Kullisaar T. Are prostatitis symptoms associated with an isoprostane-mediated vicious circle? Med Hypotheses. 2011 Nov;77(5):837-40.
- Kullisaar T, Türk S, Punab M, Mändar R. Oxidative stress--cause or consequence of male genital tract disorders? Prostate. 2012 Jun 15;72(9):977-83.
- Schwartz ES, Lee I, Chung K, Chung JM. Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain. 2008 138(3):514–24..
- Ko YK, Youn AM, Hong BH, Kim YH, Shin YS, Kang PS, Yoon KJ, Lee WH. Antinociceptive effect of phenyl N-tert-butylnitrone, a free radical scavenger, on the rat formalin test. Korean J Anesthesiol. 2012 Jun;62(6):558-64.
- Watanabe T, Inoue M, Sasaki K, Araki M, Uehara S, Monden K, Saika T, Nasu Y, Kumon H, Chancellor MB. Nerve growth factor level in the prostatic fluid of patients with chronic prostatitis/chronic pelvic pain syndrome is correlated with symptom severity and response to treatment. BJU Int. 2011 Jul;108(2):248-51.
- Hassan AA, Elgamal SA, Sabaa MA, Salem K. Evaluation of intravesical potassium sensitivity test and bladder biopsy in patients with chronic prostatitis/chronic pelvic pain syndrome. Int J Urol. 2007 Aug;14(8):738-42.
- Tsuboi N, Nishimura T, Chen H, Norose Y, Shimizu M, Kondo Y, Kimura G, Fukuda Y. Relation of leukocytosis in prostatic fluid and inflamed prostatic tissue. J Nihon Med Sch. 2007 Jun;74(3):210-6.
- Zhou Z, Hong L, Shen X, Rao X, Jin X, Lu G, et al. Detection of nanobacteria infection in type III prostatitis. Urology. 2008 71(6):1091–5.
- Türk S, Punab M, Mändar R. Antimicrobial Susceptibility Patterns of Coryneform Bacteria Isolated from Semen. Open Infect Dis J. 2009 3:31-36.
- Kładna A, Kruk I, Michalska T, Berczynski P, Aboul-Enein HY. Characterization of the superoxide anion radical scavenging activity by tetracycline antibiotics in aprotic media. Luminescence. 2011 Nov-Dec 26(6):611-5.
- Farmer MA, Chanda ML, Parks EL, Baliki MN, Apkarian AV, Schaeffer AJ. Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome. J Urol. 2011 Jul;186(1):117-24.
- US patent - US2005014847 (A1).
- Musiek ES, Brooks JD, Joo M, Brunoldi E, Porta A, Zanoni G, Vidari G, Blackwell TS, Montine TJ, Milne GL, McLaughlin B, Morrow JD. Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J Biol Chem. 2008 Jul 18;283(29):19927-35.
Silver Türk as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Microbiology
Tartu 50411, Estonia