Involvement of delta₂ opioid receptors in the development of morphine dependence in mice

The possible involvement of δ₂ opioid receptors in the development of morphine dependence was investigated using selective δ₂ receptor antagonists, naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII). The degree of morphine dependence was estimated by the ED₅₀ values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine pellet implantation. NTB administered s.c. as well as naloxone precipitated jumping and diarrhea in morphine-dependent mice. Chronic treatment with 5'-NTII (both i.c.v. and i.t. routes, 24 hr before, just before, 24 and 48 hr after morphine pellet implantation) increased the ED₅₀ values of naloxone for jumping and diarrhea. These results suggest that both supraspinal and spinal δ₂ opioid receptors are involved in the development of physical dependence on systemically administered morphine. However, chronic treatment with NTB (s.c. route, 30 min before, 24 and 48 hr after morphine pellet implantation) failed to affect the ED₅₀ values of naloxone for both withdrawal signs. These seemingly discrepant results suggest that continuous blockade of δ₂ opioid receptors (by a nonequilibrium and long- lasting antagonist, 5'-NTII) rather than intermittent blockade of δ₂ opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.