naltrindole-5--isothiocyanate and Substance-Related-Disorders

Previously, we have shown that the development of physical dependence on morphine in mice is inhibited substantially by treatment of mice with the highly selective, nonequilibrium delta-2 opioid receptor antagonist, naltrindole-5'-isothiocyanate. With the availability of the highly selective, nonequilibrium delta-1 opioid receptor antagonist, [D-Ala2,Leu5,Cys6]enkephalin, it was possible, in the present report, to examine the possible involvement of delta-1 opioid receptors in the development of opiate dependence. Mice were made physically dependent on morphine by s.c. implantation of morphine pellets (75-mg free base) for 3 days. The degree of dependence was quantified by determining the ED50 values of naloxone to precipitate withdrawal jumping and diarrhea. Neither sign of opiate withdrawal was affected by chronic treatment of animals with [D-Ala2,Leu5,Cys6]enkephalin during the morphine implant period. The data suggest that delta-1, as opposed to delta-2, opioid receptors are not involved in the development of physical dependence on morphine. This fact takes on added significance because the recently cloned delta opioid receptors appear to be the delta-2 subtype and the present data together with previous findings suggest that the cloned receptors may be proper models for the study of opiate dependence.

Topics: Affinity Labels; Animals; Diarrhea; Enkephalin, Leucine-2-Alanine; Injections, Intraventricular; Injections, Spinal; Isothiocyanates; Male; Mice; Morphine; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance-Related Disorders

The effects that naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII) have on acute morphine dependence were investigated in mice. The degree of acute dependence was estimated by the ED50 value of s.c.-administered naloxone that was required to precipitate withdrawal jumping 4 hr after s.c. injection of 100 mg/kg of morphine sulfate (MS-100). Pretreatments with NTB (10 mumol/kg, s.c., 30 min before MS-100) and 5'-NTII (10 mumol/kg, s.c., 24 hr before MS-100) increased the ED50 values of naloxone compared to those of the respective saline-treated control mice. Although NTB itself (up to 10 mumol/kg s.c.) did not precipitate jumping 4 hr after MS-100, small doses of NTB (1 and 2 mumol/kg, s.c.) administered 30 min before the challenge doses of naloxone increased substantially the ED50 value of naloxone. These results suggest that delta 2 opioid receptors are involved in acute dependence on morphine in mice.

Topics: Animals; Drug Interactions; Enkephalin, Leucine; Isothiocyanates; Male; Mice; Morphine; Naltrexone; Receptors, Opioid, delta; Substance-Related Disorders; Thiocyanates

Recently, we demonstrated that delta opioid binding sites are involved in the development of morphine tolerance and dependence. In our present work, we studied the effect of the potent and selective delta antagonist, naltrindole (NTI), and its nonequilibrium analog, naltrindole 5'-isothiocyanate (5'-NTII), on the development of morphine tolerance and dependence in mice. In the acute model, mice injected with 100 mg/kg of morphine sulfate s.c. displayed acute tolerance 4 hr later as evidenced by a greater than 3-fold increase of the ED50 of morphine sulfate when compared to that of control mice. The acute tolerance was accompanied by the development of acute physical dependence as seen by the dramatic decrease in the amount of naloxone required to precipitate withdrawal jumping. Likewise, in the chronic model s.c. implantation of morphine pellets (75 mg free base) for 3 days produced tolerance and physical dependence. The ED50 of morphine sulfate in this case was increased by about 19-fold and the amount of naloxone needed to precipitate withdrawal jumping was 40 times lower than that required for acutely dependent mice. The development of acute tolerance and dependence was suppressed markedly in mice pretreated with NTI before induction of tolerance and dependence with 100 mg/kg of morphine sulfate. Multiple administration of either NTI or 5'-NTII before and during implantation with morphine base pellets also inhibited substantially the development of morphine tolerance and dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Drug Implants; Drug Tolerance; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Indoles; Isothiocyanates; Male; Mice; Morphinans; Morphine; Naltrexone; Narcotic Antagonists; Nociceptors; Receptors, Opioid; Receptors, Opioid, delta; Substance-Related Disorders; Thiocyanates