Wednesday, January 29, 2014

Inflammatory & Neuropathic Pain

Research in neuropathic pain in endometriosis:
"Women with endometriosis and pelvic pain almost always have fine, unmyelinated nerve fibers present in the functional layer of endometrium, and these nerve fibers are also greatly increased in the myometrium. Women without endometriosis almost never have these nerve fibers. These nerve fibers may also play a role in pain generation."

"Hormones and chemicals released by endometriosis tissue also may irritate nearby tissue and cause the release of other chemicals known to cause pain....Some endometriosis lesions have nerves in them, tying the patches directly into the central nervous system. These nerves may be more sensitive to pain-causing chemicals released in the lesions and surrounding areas. Over time, they may be more easily activated by the chemicals than normal nerve cells are. Patches of endometriosis might also press against nearby nerve cells to cause pain."

"Blood vessels are innervated by sensory and sympathetic fibres; thus when blood vessels branch to vascularise developing lesions, termed angiogenesis, nerves innervating those blood vessels may also branch (neural sprouting), thereby enabling nerves to invade lesions. Zhang et al suggest that endometriosis is a neurovascular condition much like headache, a concept that was also suggested clinically....Prolonged noxious stimulation of the viscera, for example in a distended bladder, which is normally not a painful stimulus, can evoke increased excitability of viscerosomatic neurones in the spinal cord and subsequently cause pain. Once triggered, this central sensitisation is sustained despite the termination of noxious input, demonstrating that pain may be experienced even in the absence of peripheral noxious stimuli....This establishes central hypersensitivity whereby normal sensory stimuli, in a magnified form, are perceived as pain. This may also result in muscle hyperalgesia, as muscles are closely related to viscera and the nerves. There is also an implication of chemical changes, for example in the central neuromodulator N-Methyl-D-aspartate.
There is also evidence that painful endometriosis can be classified as a mixed inflammatory and neuropathic pain condition or a neurovascular condition, both of which open new avenues for pain relief.

"Although about ten years ago it had been noted that pain can be more severe in patients whose ectopic growths are located near or in richly innervated anatomical sites (rectovaginal septum, uterosacral ligaments) than in patients whose growths invaded less densely innervated tissue (peritoneum and/or ovaries) [4], [5], scant attention was paid to this finding regarding nerves; research and drug development remained focused on the ectopic growths and their immediate external environment (e.g., peritoneal fluid and local inflammation) as the source of the pain....Our group discovered that ectopic growths harvested from ENDO rats and women with established endometriosis develop their own C-fiber (sensory afferent) and sympathetic (autonomic efferent) nerve supply. The supply is derived from nerve fibers innervating nearby territories that sprout branches into the growths [10], [11]. This discovery suggests that, rather than the growths alone, it is the ectopic growth's own innervation that is a major contributor to the maintenance and modulation of pain in established endometriosis [12]. It remains unknown, however, whether this sprouted and thereby abnormal innervation contributes to the initial development of endometriosis-associated pain. If so, painful endometriosis, now recognized as an inflammatory condition [3], could also be considered within the realm of neural dysfunction, i.e., a mixed inflammatory and neurogenic pain, which would alter clinical approaches to the pain.... Our findings strongly support the hypothesis that the invasion of the cysts by sensory and sympathetic fibers is a major contributor to the development of endometriosis-associated pain, which suggests an aggressive clinical strategy of prevention."

In reference to the above study, this article was written by Chandler Marrs, PHD for 

"If the innervation is associated with endometrial pain, it is possible that curtailing the nerve growth could eliminate, even prevent the pain, but only if this disease process is identified early enough.
In the rat model, innervation developed in phases.  Within the first two weeks of the tissue implant, a cyst developed and initial sensory and sympathetic nerves sprouted.  Over the next weeks, the nerve sprouts became functional and neurogenic inflammation developed. Finally, over weeks four and five, the cysts became wholly populated by functional sympathetic and sensory nerve fibers. Pain ensued. Researchers found that removing the cysts before they reached the functional stage prevented the development of neuropathic pain- the vaginal hyperalgesia.

Although it is not clear what the time course of cyst innervation would be in human women -for rats the entire estrous cycle is 4-5 days, significantly shorter than the female menstrual cycle- it is clear that efforts should be made to identify and diagnose endometriosis significantly sooner than is currently the average.

That would require investigating the causes of dysmenorrhea and not automatically attributing the pain with menstruation to normal premenstrual or menstrual cramping, as is so often the case. Currently, the average time to diagnose endometriosis is nine years. Research suggests that 90% of adolescent girls have dysmenorrhea and 25-38% of adolescent girls with chronic pelvic pain have endometriosis.

If cyst development stages could be identified in women and if endometriosis diagnosed earlier, then removing or treating cysts before fully innervated could prevent a lifetime of what we now know to be neuropathic pain....Though many are loathe to admit it, hormones are likely involved. In many regions of the brain hormones elicit and modulate neurogenesis. Research also demonstrates a role for hormones in spinal and peripheral nerve functioning. As results from this study suggest, hormones may also influence somatosensory nerve growth in the uterine and extra-uterine endometrial tissue. Understanding the role of hormones in the innervation of endometrial tissue could open up entirely new therapeutic options."