Modulation of μ-mediated antinociception by δ agonists: characterization with antagonists

The functional interactions between supraspinal μ and δ receptors were characterized in the mouse using μ receptor-selective antagonists. The effects of pretreatment with the μ opioid antagonists, β-funaltrexamine (β-FNA) and naloxonazine on the modulation of morphine antinociception by the δ 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 δ antagonist. Pretreatment of mice with the non-equilibrium μ antagonist β-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 μ₁ 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 μ-δ receptor complex which is sensitive to antagonism by β-FNA, but not naloxonazine, and support the notion that subtypes of opioid μ and δ (i.e. complexed and non-complexed) receptors may exist.