Anti-nociceptive actions of neurotrophin-3 and estrogen in an acid-induced model of chronic pain in mice

The purpose of this study was to determine the efficacy of neurotrophins, in particular NT-3, in reducing chronic pain states in mice. Furthermore, the importance of changes in estrogen status in maintaining chronic pain states was also investigated. These studies were performed by utilizing an animal model of acid-induced mechanical hyperalgesia that displays similar characteristics as those found in clinical syndromes such as Fibromyalgia, Irritable Bowel Syndrome, and diseases that display referred hypersensitivity to mechanical stimuli. The goal of this dissertation was to investigate, and thereby establish, anti-nociceptive actions for neurotrophins and estrogen in chronic pain states.; Injection of acidic saline led to increased paw withdrawals (hyperalgesia) to a mechanical, but not thermal, stimulus. This increase in hyperalgesia strongly correlated with an upregulation of Fos expression in superficial dorsal horn laminae in the spinal cord, indicative of an increase in the activity of these spinal neurons. Over-expression of NT-3 in skeletal muscle reduced acid-induced hyperalgesia and Fos expression, compared to wild-type littermates. This anti-nociceptive effect was mimicked in wild-type mice with intramuscular treatment of exogenous human NT-3, but not NGF, BDNF or GDNF.; Estrogen replacement, both in the form of slow-release pellets and a single injection, abolished the ability of acid to increase paw withdrawals to mechanical stimuli. This analgesic effect appears to be mediated via the ER-alpha receptor since a single injection of PPT, a selective ER-alpha agonist, prevented acid-induced mechanical hyperalgesia, whereas DPN, a selective ER-beta agonist, was ineffective in reducing the hyperalgesia. Interestingly, the analysis of skeletal muscle from estrogen-treated mice demonstrated an increase in NT-3 mRNA levels, suggesting a possible synergistic mechanism of action between estrogen and NT-3.; Finally, these studies identify a specific subpopulation of DRG neurons that may mediate the anti-nociceptive effects of NT-3 and estrogen. These neurons express TrkC and ASIC-3, and innervate blood vessels in skeletal muscle. It is proposed that NT-3 and estrogen have possible synergistic effects in reducing acid-induced mechanical hyperalgesia. Together, these data suggest that NT-3 and estrogen have the ability to reduce acid-induced hyperalgesia in muscle and could be potential targets for the burgeoning field of pain medicine.