Modulation of [mu]-mediated antinociception by [delta] agonists: characterization with antagonists

Abstract

The functional interactions between supraspinal [mu] and [delta] receptors were characterized in the mouse using [mu] receptor-selective antagonists. The effects of pretreatment with the [mu] opioid antagonists, [beta]-funaltrexamine ([beta]-FNA) and naloxonazine on the modulation of morphine antinociception by the [delta] agonists [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2, Met5]enkephalinamide (DAMA) were studied. When co-administered in the same i.c.v. injection, a sub-antinociceptive dose of DPDPE consistently and significantly increased the antinociceptive potency of morphine in control animals, while a sub-effective dose of DAMA decreased morphine antinociception; both the respective increase and the decrease of morphine potency by DPDPE and DAMA had been previously shown to be blocked by ICI 174,864, a [delta] antagonist. Pretreatment of mice with the non-equilibrium [mu] antagonist [beta]-FNA 4 h prior to testing, a pretreatment which had no effect on i.c.v. DPDPE or DAMA antinociception, prevented the modulation of morphine antinociception by both DPDPE and DAMA. Pretreatment with the long acting [mu]1 antagonist naloxonazine, 24 h prior to testing, failed to affect the modulation of morphine antinociception by either DPDPE or DAMA; such a pretreatment had no effect on the antinociceptive effects of DPDPE or DAMA when given alone. These results provide further support for the concept of a functionally coupled [mu]-[delta] receptor complex which is sensitive to antagonism by [beta]-FNA, but not naloxonazine, and support the notion that subtypes of opioid [mu] and [delta] (i.e. complexed and non-complexed) receptors may exist.