Opioid δ-receptor involvement in supraspinal and spinal antinociception in mice

The possibility that the opioid δ-receptor mediates antinociception in tests where heat is the noxious stimulus was investigated using highly selective μ- and δ-agonists and -antagonists. Antinociceptive dose-response curves were constructed for μ ([d-Ala², NMePhe⁴, Gly-ol]enkephalin, DAGO; morphine) and δ ([d-Pen²,d-Pen⁵]enkephalin, DPDPE)-agonist in the absence, and in the presence of the μ non-surmountable antagonist, β-funaltrexamine (β-FNA) or the δ-antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu- OH, where Aib is α-amino-isobutyric acid). Agonists and ICI 174,864 were given alone or in the same intracerebroventicular (i.c.v.) or intrathecal (i.th.) injection to mice 20 min prior to testing in the warm-water (55 °C) tail-withdrawal test (+10 min for i.th. DPDPE); β-FNA was given as a single i.c.v. or i.th. pretreatment dose (20 and 0.01 nM, respectively) 4 hr with β-FNA resulted in a rightward displacement of the DAGO and morphine antinociceptive dose-response lines, but failed to displace the i.c.v. DPDPE curve. Similarly, i.th. pretreatment with β-FNA displaced the i.th. morphine dose-response curve to the right without affecting the i.th. DPDPE antinociceptive dose-response line. ICI 174,864 (1 and 3 μg) produced a dose-related antagonism of i.c.v. or i.th. DPDPE, but did not alter the antinociceptive effects of DAGO or morphine given by the same routes. Co-administration of ICI 174 864 (μg) i.c.v. morphine in β-FNA pretreated (but not control) mkce resulted in a further rightward displacement of the morphine dose-response line. The effective antagonism of DPDPE but not morphine or DAGO antinociception by ICI 174,864, together with the effectiveness of β-FNA against morphine and DAGO but not DPDPE antinociception, provide strong and direct evidence for the involvement of cerebral and spinal δ-receptors in the mediation of antinociception in tests where heat is employed as the noxious stimulus. Additionally, the effectiveness of ICI 174,864 against morphine in β-FNA pretreated (but not control) mice demonstrates a δ-effect of morphine, in vivo.