Broad-Spectrum, Non-Opioid Analgesic Activity by Selective Modulation of Neuronal Nicotinic Acetylcholine Receptors

• Published in: Science (American Association for the Advancement of Science) Vol. 279; no. 5347; pp. 77 - 81
• Main Authors: Bannon, A. W., Decker, M. W., Holladay, M. W., Curzon, P., Donnelly-Roberts, D., Puttfarcken, P. S., Bitner, R. S., Diaz, A., Dickenson, A. H., Porsolt, R. D., Williams, M., Arneric, S. P.
• Format: Journal Article
• Language: English
• Published: United States American Society for the Advancement of Science 02-01-1998; The American Association for the Advancement of Science
• Subjects: Analgesics; Analgesics, Non-Narcotic - chemical synthesis; Analgesics, Non-Narcotic - metabolism; Analgesics, Non-Narcotic - pharmacology; Anatomy; Animal models; Animals; Azetidines - chemical synthesis; Azetidines - metabolism; Azetidines - pharmacology; Body Weight; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Capsaicin - pharmacology; Dose-Response Relationship, Drug; Drugs; In Vitro Techniques; Inhibition; Ligands; Mecamylamine - pharmacology; Medical research; Morphine; Morphine - pharmacology; Narcotics; Nerve Fibers - drug effects; Nerve Fibers - metabolism; Nerve Fibers - physiology; Neuromuscular Junction - metabolism; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Nicotine - pharmacology; Nicotinic Agonists - chemical synthesis; Nicotinic Agonists - metabolism; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - pharmacology; Opioid analgesics; Pain; Pain - drug therapy; Pain Measurement; Pain measurement scales; Pretreatment; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - pharmacology; Rats; Receptors, Nicotinic - metabolism; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiology; Substance Withdrawal Syndrome - etiology; Synaptic Transmission - drug effects
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.279.5347.77

Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of actue thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.