title: A role for spinal, but not supraspinal, alpha(2) adrenergic receptors in the actions of improgan, a powerful, non-opioid analgesic.
abstract: Improgan is a derivative of cimetidine that induces non-opioid antinociception after intracerebroventricular (i.c.v.) administration, but the mechanism of action of this compound remains unknown. Since activation of either supraspinal or spinal alpha(2) adrenergic receptors can induce antinociception, and since improgan showed affinity for these receptors in vitro, the effects of the alpha(2) antagonist yohimbine on improgan antinociception were presently studied in rats on the hot plate and tail flick tests. Systemic yohimbine pretreatment (4 mg/kg, i.p.) completely blocked improgan antinociception (80 microg, i.c.v.), suggesting a mediator role for alpha(2) receptors. However, i.c.v. pretreatment with yohimbine (30 microg) had no effect on improgan antinociception. Since this treatment completely antagonized clonidine antinociception (40 microg, i.c.v.), supraspinal alpha(2) receptors seem to mediate the antinociceptive effects of clonidine, but not that produced by improgan. In contrast, intrathecal (i.t.) yohimbine pretreatment (30 microg) completely blocked the antinociception elicited by i.c.v. improgan and i.c.v. morphine. These results suggest that spinal (but not supraspinal) alpha(2) adrenergic receptors play a significant role in the pain-relieving actions of improgan. Furthermore, although improgan shows some affinity at alpha(2) receptors, this drug does not act directly at these receptors to induce antinociceptive responses. Like several other classes of analgesics, improgan-like drugs seem to activate non-opioid, descending pain-relieving circuits.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College MC-136, Albany, NY 12208, USA.
authors.forename: K
authors.initials: K
authors.lastname: Svokos
authors.forename: J W
authors.initials: JW
authors.lastname: Nalwalk
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.forename: W M
authors.initials: WM
authors.lastname: Menge
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
authors.forename: L B
authors.initials: LB
authors.lastname: Hough
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; C099531:SKF 92374; D015016:Yohimbine; D009020:Morphine; D002927:Cimetidine; D003000:Clonidine