Pathological pain often manifested as hypersensitivity to noxious (hyperalgesia) and non-noxious (allodynia) stimuli, is associated with long-term changes in the neurochemical modulators of spinal nociceptive transmission. For example, nerve injury profoundly up-regulates the synthesis of NPY in DRG neurons and the spinal release of neuropeptide Y (NPY), and inflammation increases the number and distribution of dorsal horn neurons containing Y I receptor rnRNA. In studies in our laboratory designed to address the functional consequences of these changes, it was discovered that NPY inhibits nociceptive behavior in well-established animal models of acute inflammation (intraplantar formalin injection), arthritic pain (complete Freund?s adjuvant) and peripheral neuropathic pain (Seltzer model of nerve injury). Based on these data, the long-term objective of this project is to test the overall hypothesis that inflammatory or sensory nerve injury increases presynaptic and postsynaptic elements of NPY signaling at the dorsal horn, thereby inhibiting pronociceptive neurotransmission, and ultimately decreasing allodynia and hyperalgesia. To test the sub-hypothesis that NPY inhibits allodynia and hyperalgesia in animal models of inflammatory and neuropathic pain, Specific Aim #1 will determine the contribution of Yl or Y2 receptors to the actions of NPY using new receptor subtype-selective antagonists and deletion mutant mice lacking the NPY, Yl or Y2 gene. To evaluate the effects of inflammation or nerve injury on NPY release and NPY Y1 receptor expression, and to correlate these with the magnitude of nociceptive behaviors.
Specific Aim #2 will use in vivo microdialysis and immunohistochemistry to assess the effects of injury on NPY content in cerebrospinal fluid from the lumbar intrathecal space, Yl-like immunoreactivity in nociceptive regions of the dorsal horn, and nociceptive behavior at multiple time-points. To test the hypothesis that NPY inhibits spinal nociceptive transmission, Specific Aim #3 will evaluate the effects of intrathecal NPY and/or newly-developed NPY receptor antagonists on the activity of spinal nocicresponsive neurons (using c-fos immunocytochemistry) and the spinal release of substance P. The latter will be evaluated with in vivo microdialysis, as well as with quantification of neurokinin 1 receptor internalization, which determines neurokinin release in terms of receptor activation, laminar distribution, and target neuron morphology. An understanding of the endogenous compensatory mechanisms that contribute to the intrinsic decay of aberrant nociceptive signaling may help us to identify new drugs for the treatment of pathological pain.
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