Antinociceptive and behavioral effects of synthetic deltorphin analogs

A possible correlation of behavioral, antinociceptive and cataleptic responses with central delta- and mu-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 delta-opioid receptor agonist, [D-Ala(2),Glu(4)]deltorphin (Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2), 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 delta-selectivity because of a gain in mu-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 mu and delta antagonists, the non-selective mu-opioid receptor antagonist, naloxone (1 mg/kg i.p.), reduced analgesia and abolished the initial hypolocomotion. The delta-selective antagonist, naltrindole (10 mg/kg i.p.), abolished locomotor activity without affecting analgesia. The mu(1)-selective antagonist, naloxonazine (10 mg/kg i.v.), seemed to prolong analgesia and immobility. Hence this peptide appears to activate, in addition to delta-receptors, mainly the opioid receptor mu(2)-subtype, which mediates catalepsy in the rat. We suggest that the mu(2)- and delta-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 mu-affinity. A possible explanation might be a mu/delta-opioid receptor interaction.