Spinal and supraspinal agmatine activate different receptors to enhance spinal morphine antinociception.
The endogenous clonidine-displacing substance, agmatine, enhances morphine-induced antinociception and inhibits development of tolerance to morphine. Because agmatine binds with relatively high affinity to both alpha(2) adrenergic and imidazoline (I) receptors, the following studies were designed to determine which receptor type is involved in the morphine-enhancing activity. Mice were injected by various routes with agmatine, clonidine or norepinephrine as well as selective antagonists, and tail flick antinociception was measured. Agmatine administered subcutaneously (s.c.), intracerebroventricularly (i.c.v.), or intrathecally (i.t.) had no antinociceptive activity, but enhanced the antinociception produced by i.t. morphine. The morphine-enhancing activity of i.c.v. agmatine (and clonidine) was attenuated by coadministered yohimbine, idazoxan and SK and F 86466 (alpha(2) antagonists). When given i.t., agmatine, yohimbine and SK and F 86466 attenuated the antinociception produced by coadministered i.t. clonidine. In contrast, i.t. yohimbine and SK and F 86466, but not agmatine, attenuated antinociception produced by i.t. norepinephrine. These results suggested that agmatine actions were different at brain and spinal sites. Thus, agmatine may act at both alpha(2) and I receptors in the brain and I receptors in the spinal cord.
Roerig
Sandra C
SC
Department of Pharmacology and Therapeutics, LSU Health Sciences Center, Shreveport, Louisiana 71130, USA. sroeri@lsuhse.edu
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000376:Agmatine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010147:Pain Measurement; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; D000376:Agmatine; D009020:Morphine; D003000:Clonidine; D009638:Norepinephrine