Antinociceptive and behavioral effects of synthetic deltorphin analogs

Abstract

A possible correlation of behavioral, antinociceptive and cataleptic responses with central δ- and μ-opioid receptor stimulation was tested for in the rat by i.c.v. injections of some synthetic deltorphin analogs. At doses ranging from 0.1 to 3.0 nmol/rat, the selective δ-opioid receptor agonist, [ d-Ala 2,Glu 4]deltorphin (Tyr- d-Ala-Phe-Glu-Val-Val-Gly-NH 2), induced a dose-dependent stereotyped pattern of locomotor activity, reaching the maximum in the first 30 min; doses higher than 30 nmol induced early and fleeting antinociception. The replacement of Glu 4 by Gly, Ala, Val, His or Asn yielded peptides with a lower δ-selectivity because of a gain in μ-affinity. [ d-Ala 2,Ala 4]deltorphin (0.14–4.0 nmol) induced negligible behavioral stimulation but a rapidly appearing and long-lasting analgesia and catalepsy. The other four synthetic peptides induced biphasic effects: low dosages stimulated locomotion whereas higher doses initially suppressed, then increased locomotor activity. At doses ranging from 1 to 70 nmol all the peptides induced analgesia and catalepsy. In experiments examining the locomotor and antinociceptive effects induced by 14 nmol of [ d-Ala 2,Gly 4]deltorphin in rats pretreated with μ and δ antagonists, the non-selective μ-opioid receptor antagonist, naloxone (1 mg/kg i.p.), reduced analgesia and abolished the initial hypolocomotion. The δ-selective antagonist, naltrindole (10 mg/kg i.p.), abolished locomotor activity without affecting analgesia. The μ 1-selective antagonist, naloxonazine (10 mg/kg i.v.), seemed to prolong analgesia and immobility. Hence this peptide appears to activate, in addition to δ-receptors, mainly the opioid receptor μ 2-subtype, which mediates catalepsy in the rat. We suggest that the μ 2- and δ-opioid receptors of the rat brain modulate locomotor behavior by activating functionally opposed responses. [ d-Ala 2,Ala 4]deltorphin had an antinociceptive and cataleptic potency higher than would have been expected from its μ-affinity. A possible explanation might be a μ/δ-opioid receptor interaction.