The purpose of this renewal proposal, for a third cycle of funding, is to test specific hypotheses concerning the relevance of animal studies to the spinal pharmacology of pain and analgesia in humans. The goal for the next project period is to concentrate on adenosine as a potential agent for the relief of neuropathic pain. In preliminary animal studies, adenosine has been found to be selectively effective in allodynia versus acute pain.
Two specific aims relate to this: (1) in human studies, define the dose-response and time course of intrathecal adenosine alone and with clonidine for side effects, analgesia to an acute thermal stimulus, and inhibition of capsaicin-induced mechanical allodynia and hyperalgesia in volunteers, and adenosine's efficacy as an analgesic in patients with chronic neuropathic pain; (2) in animal studies, test pharmacokinetic and pharmacodynamic mechanisms for adenosine's greater potency to remove allodynia than to block acute nociceptive stimuli, and examine pharmacologic mechanisms for the interaction between adenosine and a2 adrenoceptor-mediated neurotransmission in spinal cord. Hypotheses to be tested for pharmacodynamic mechanisms include allodynia-induced changes in adenosine receptor number or affinity, in adenosine-induced norepinephrine release, and in adenosine inhibition of excitatory amino acid release. Although only the animal studies are described in detail, a test of the adenosine-clonidine combination in human subjects is apparently also envisioned. A third specific aim is to complete preclinical neurotoxicity screening for preservative-free ketorolac in animals prior to human intrathecal testing.
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