The treatment of pain is a critical health issue affecting tens of millions of people annually in the US. Chronic pain (cancer and nonmalignant pain) management is an especially challenging task. The primary groups of agents that have been used to treat pain are the opioids (eg. morphine) and the nonsteroidal antiinflammatory drugs (NSAID's; eg. ibuprofen, celecoxib). Significant limitations related to side effects and efficacy, most notably for chronic neuropathic pain syndromes (eg. diabetic neuropathy, AID's related neuropathy, complex regional pain syndrome, spinal cord injury) exist with these two classes of drugs. New therapeutic agents for pain with an improved efficacy/side effect profile would result in significant societal benefit. Drugs acting at nicotinic acetylcholine receptors are a potentially important new class of analgesic drugs. One such drug, nornicotine, an active metabolite of nicotine, is a promising analgesic candidate. This drug has both a better pharmacokinetic profile (longer half-life, accumulation in the CNS, greater bioavailability) and less toxicity compared to nicotine. Nornicotine has both S(-)- and R(+) enantiomeric forms and the enantiomers appear to differ in analgesic potency and side effects. Thus, it is reasonable to expect that one enantiomer will possess greater analgesic efficacy with acceptable side effects. Our preliminary findings support this possibility and precedent exists for this concept with other analgesic drugs (eg. N-methyl-D- aspartate receptor antagonists). The major goal of this Phase I STTR study is to examine antinociceptive, anti- hyperalgesic and anti-allodynic activity of S(-)- and/or R(+)-nornicotine in rodent models of acute (thermal paw withdrawal), tonic inflammatory (intraplantar formalin injection) and neuropathic pain (sciatic nerve constriction). Locomotor activity and motor coordination (rotorod) will also be examined to determine if the antinociceptive activity of the nornicotine enantiomers occurs without significant motor impairment. Finally, we will determine if there is a synergistic (supra-additive) antinociceptive effect produced when S(-)- and/or R(+)- nornicotine is used in combination with an opioid (morphine). Multi-drug approaches to pain management are clinically well established and such a combination utilizes lower doses of each drug and would be expected to diminish side effects associated with each agent. The Specific Aims are to: 1) Characterize the antinociceptive, anti-hyperalgesic and anti-allodynic effects of S(-)- and R(+)-nornicotine in a rat model of nociceptive, neuropathic and tonic inflammatory pain; 2) Characterize the effects of S(-)- and R(+)-nornicotine on locomotor activity and motor coordination; 3) Characterize the synergistic antinociceptive effect of morphine in combination with S(-)- and R(+)-nornicotine in a rat model of nociceptive pain and 4) Perform synthesis of S(-)- and R(+)-nornicotine for use in the preclinical antinociception and side effect studies. Findings from this Phase I STTR study are important to the long term goal (Phase II studies) of developing a clinically useful analgesic drug (nornicotine enantiomer) suitable for management of pain. The treatment of pain is a critical health issue affecting tens of millions of people annually in the US. New therapeutic agents for pain, especially for chronic pain (cancer-related and nonmalignant) would result in significant societal benefit. This research project focuses on the development of a novel analgesic agent, nornicotine, for pain management.
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