Spinal delta-opioid receptors mediate suppression of systemic SNC80 on excitability of the flexor reflex in normal and inflamed rat

Abstract

Due to low central nervous system (CNS) bioavailability of delta-opioid peptides, little is known about the effect of systemic administration of delta-opioid receptor ligands. The present study examined the effect of non-peptidergic delta-opioid receptor agonists, (+)-4-[(alphaR)-alpha-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) and (-)dibenzoyl-L-tartaric acid salt (SNC86), on the activity of alpha-motoneurons in decerebrate-spinal rats. The flexor reflex was facilitated by C-afferent conditioning inputs, shown by a decrease in mechanical threshold and increase in touch- and pinch-evoked responses. Systemic administration of SNC80 (10 micromol/kg) prevented and reversed the neuronal hyperactivity. We further examined the effect of this agonist on the hypersensitivity of the flexor reflex induced by intraplantar injection of Freund's adjuvant. SNC80 dose-dependently (1, 3, 5 and 10 micromol/kg) increased the mechanical threshold and decreased touch-, pinch- and Abeta-afferent inputs-evoked responses. Similar effects were seen with SNC86 (5 micromol/kg). Pretreatment with either naloxone (20 micromol/kg, i.p.) or (Cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-14beta-ethoxy-5beta-methylindolo [2',3':6',7']morphinan-3-ol hydrochloride (SH378; 5 micromol/kg, intraarterially (i.a.)), a novel selective delta-opioid receptor antagonist, completely abolished the anti-hypersensitivity effect of SNC80. The effect of SNC80 remained following intrathecal administration of mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP; 1.5 nmol). These results indicate that systemic injection of SNC80 exerted antihypersensitivity in models of both acute and tonic nociception and these effects are mediated mainly through a spinal delta-opioid mechanism.