Supraspinal opioid delta receptor subtypes: Involvement in direct and modulatory antinociceptive functions

Abstract

The discovery of endogenous opioid peptides and multiple opioid receptors may lead to a new avenue in understanding the mechanisms of opioid action and treatment of pain. The specific aims of the present study are to determine whether (1) subtypes of the opioid δ receptor exist; (2) if antinociceptive efficacy of μ agonists is modulated by δ agonists; and (3) if development of morphine tolerance and dependence is reduced by co-administration of μ and δ agonists producing equivalent antinociception to that achieved with μ agonists alone. The antinociceptive effect of opioid agonists was measured using warm water mouse tail flick assay. Intracerebroventricular (i.c.v. administration of the δ agonists, (D-Pen², D-Pen⁵) enkephalin (DPDPE), (D-Ser², Leu⁵, Thr⁶) enkephalin (DSLET), (D-Ala², Leu⁵, Cys⁶) enkephalin (DALCE), or deltorphin II produced antinociceptive effects, which were blocked by the δ antagonist ICI 174,864. Following pretreatment, DALCE also produced antagonism of DPDPE and DALCE, but not deltorphin II and DSLET induced antinociception. The antinociceptive effects of DSLET and deltorphin II, but not of DPDPE and DALCE, were antagonized by naltrindole-5'-isothiocyanate (5'-NTII), a δ antagonist. Sub-antinociceptive doses of DPDPE, DSLET, and deltorphin II positively modulated morphine antinociception. The modulation was blocked by ICI 174,864 or 5'-NTII. DALCE produced neither modulation of morphine antinociception as a δ agonist, nor antagonism of the modulatory effects of DPDPE, DSLET, and deltorphin II as a δ antagonist. Under conditions of high stimulus intensity, morphine acted as a partial agonist; morphine efficacy was increased to the level of a full agonist in the presence of sub-antinociceptive doses of δ agonists, such as (Leu⁵) enkephalin, DPDPE, or the neutral endopeptidase inhibitor, thiorphan. Again, these modulatory effects were antagonized by i.c.v. ICI 174,864. In the presence of sub-antinociceptive dose of DPDPE or (Leu⁵) enkephalin, morphine produced antinociception equivalent to that of a higher dose of morphine, and antinociceptive tolerance and dependence developed more slowly. These data demonstrate the existence of subtypes of δ receptor, i.e., DALCE sensitive and 5'-NTII sensitive δ receptors. In addition, morphine antinociception can be positively modulated by δ agonists without increasing the rate of development of antinociceptive tolerance and physical dependence.