Due to low central nervous system (CNS) bioavailability of δ-opioid peptides, little is known about the effect of systemic administration of δ-opioid receptor ligands. The present study examined the effect of non-peptidergic δ-opioid receptor agonists, (+)-4-[(α R)-α-((2 R,5 R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N, N-diethylbenzamide (SNC80) and (−)dibenzoyl- l-tartaric acid salt (SNC86), on the activity of α−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 μmol/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 μmol/kg) increased the mechanical threshold and decreased touch-, pinch- and Aβ-afferent inputs-evoked responses. Similar effects were seen with SNC86 (5 μmol/kg). Pretreatment with either naloxone (20 μmol/kg, i.p.) or (Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14β-ethoxy-5β-methylindolo [2′,3′:6′,7′]morphinan-3-ol hydrochloride (SH378; 5 μmol/kg, intraarterially (i.a.)), a novel selective δ-opioid receptor antagonist, completely abolished the anti-hypersensitivity effect of SNC80. The effect of SNC80 remained following intrathecal administration of μ-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 δ-opioid mechanism.
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