Neural basis for improgan antinociception

• Published in: Neuroscience Vol. 169; no. 3; pp. 1414 - 1420
• Main Authors: Heinricher, M.M, Martenson, M.E, Nalwalk, J.W, Hough, L.B
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.09.2010; Elsevier
• Subjects: Action Potentials; Analgesics; Analgesics, Non-Narcotic - administration & dosage; Analgesics, Non-Narcotic - pharmacology; Animals; Biological and medical sciences; brainstem; Cimetidine - administration & dosage; Cimetidine - analogs & derivatives; Cimetidine - pharmacology; Fundamental and applied biological sciences. Psychology; Injections, Intraventricular; Male; Medulla Oblongata - drug effects; Medulla Oblongata - physiopathology; Neurology; Neurons - drug effects; Neurons - physiology; OFF-cells; ON-cells; Pain - drug therapy; Pain - physiopathology; pain-modulation; Rats; Rats, Sprague-Dawley; Reaction Time; rostral ventromedial medulla; Vertebrates: nervous system and sense organs; OFF-cells; TF; pain-modulation; N-methyl- d-aspartate; tail flick; i.c.v; NMDA; RVM; intracerebroventricular; brainstem; rostral ventromedial medulla; ON-cells; Analgesia; Pain; Brain stem; Central nervous system; Encephalon
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.05.042

Abstract Improgan, the prototype compound of a novel class of non-opioid analgesic drugs derived from histamine antagonists, attenuates thermal and mechanical nociception in rodents following intracerebroventricular (i.c.v.) administration. Improgan does not bind to known opioid, histamine or cannabinoid receptors, and its molecular target has not been identified. It is known however, that improgan acts directly in the periaqueductal gray and the rostral ventromedial medulla to produce its antinociceptive effects, and that inactivation of the rostral ventromedial medulla prevents the antinociceptive effect of improgan given i.c.v. Here we used in vivo single-cell recording in lightly anesthetized rats to show that improgan engages pain-modulating neurons in the medulla to produce antinociception. Following improgan administration, OFF-cells, which inhibit nociception, became continuously active and no longer paused during noxious stimulation. The increase in OFF-cell firing does not represent a non-specific neuroexcitant effect of this drug, since ON-cell discharge, associated with net nociceptive facilitation, was depressed. NEUTRAL-cell firing was unaffected by improgan. The net response of rostral ventromedial medulla (RVM) neurons to improgan is thus comparable to that evoked by μ-opioids and cannabinoids, well known RVM-active analgesic drugs. This common basis for improgan, opioid, and cannabinoid antinociception in the RVM supports the idea that improgan functions as a specific analgesic agent.