Mu- and kappa-opioid receptor agonists produce peripheral inhibition of neurogenic plasma extravasation in rat skin

Abstract

Extravasation elicited in rat skin by antidromic electrical stimulation of the saphenous nerve was dose dependently inhibited by the intravenous (i.v.) application of the mu-opioid receptor agonists, morphine and [D-Ala2,Me-Phe4,Gly-ol5]enkephalin (DAGO), and the kappa-opioid receptor agonists (-)-U 50488H, (-)-ICI 197067 and ICI 204448. This inhibition was antagonised by naloxone, and the lack of action of (+)-U 50488H (5 mg/kg) indicated that the kappa effect was stereoselective. The delta-opioid receptor agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE), and the sigma-receptor agonist, (+)-SKF 10047, had no effect on neurogenic extravasation at a dose of 5 mg/kg. Opiate-induced changes in cutaneous blood flow were not important for opiate inhibition since extravasation produced by exogenous substance P (the putative neurotransmitter) was not influenced by the opiates. An indirect opiate action via the adrenal glands was excluded since the effectiveness of DAGO, (-)-ICI 197067 and ICI 204448 was unchanged after adrenalectomy. Finally, the cutaneous locus of the opiate effect was shown by blocking the activity of systemically applied DAGO and ICI 204448 with naloxone injected into paw. These results indicate that specific mu-opioid and kappa-opioid, but not delta-opioid and sigma receptor agonists, inhibit neurogenic plasma extravasation in rat skin, probably via opioid receptors on peripheral terminals of sensory C-fibres.