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Spinal and Supraspinal Agmatine Activate Different Receptors to Enhance Spinal Morphine Antinociception

Abstract: 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 a2 adrenergic and inidazoline (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&F 86466 (a2 antagonists). When given i.t., agmatine, yohimbine and SK&F 86466 attenuated the antinociception produced by coadministered i.t. clonidine. In contrast, i.t. yohimbine and SK&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 a2 and I receptors in the brain and I receptors in the spinal cord.