Functional interaction among opioid receptor types: up-regulation of μ- and δ-opioid receptor functions after repeated stimulation of κ-opioid receptors

Abstract

It has been widely accepted that repeated administration of κ-opioid receptor agonists leads to the development of antinociceptive tolerance. The present study was designed to investigate the effect of repeated administration of a selective κ-opioid receptor agonist (1 S- trans)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride ((−)U-50,488H) on the μ- and δ-opioid receptor agonist-induced antinociception and G-protein activation in mice. The mice were injected either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) pretreated with saline or (−)U-50,488H once a day for seven consecutive days. Two hours after the last injection, the mice were challenged by either μ- or δ-opioid receptor agonist for the antinociceptive assay. Repeated treatment with (−)U-50,488H (s.c. or i.c.v.) significantly enhanced antinociceptive effect of both μ-opioid recep tor agonist (morphine) and δ-opioid receptor agonists ([ d-Ala 2]deltorphin (DELT) and (+)-4-[(α R)-α-((2 S,5 R)-4-allyl-2,5-dime thyl-1-piperazinyl)-3-methoxybenzyl]- N, N-diethylbenzamide (SNC-80) compared to saline-treated groups. Under these conditions, repeated s.c. injection of (−)U-50,488H significantly enhanced both μ- and δ-opioid receptor agonist-stimulated [ 35S]GTPγS binding in the membrane of the thalamus. On the contrary, either repeated administration of morphine (s.c. or i.c.v.) or SNC-80 failed to affect the κ-opioid receptor agonist-induced antinociception and G-protein activation. Taken together, these results suggest that repeated stimulation of κ-opioid receptor markedly increases the functional μ- and δ-opioid receptors, whereas repeated stimulation of either μ- or δ-opioid receptor had no direct effect on κ-opioidergic function in mice.