naltrindole-5--isothiocyanate and naltrindole-benzofuran

This study examined the contribution of spinal delta1 and delta2 opioid receptors to the antinociception produced by microinjection of L-glutamate in either the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars alpha (NGCp alpha) of the rat. Intrathecal (i.t.) pretreatment with 1 microg of 7-benzylidinenaltrexone (BNTX), a delta1 opioid receptor antagonist, did not antagonize the increase in tail flick latency (TFL) produced by microinjection of L-glutamate in either the NRM or the NGCp alpha. In contrast, i.t. pretreatment with 3 microg of naltriben (NTB), a delta2 opioid receptor antagonist, completely antagonized the increase in TFL evoked by microinjection of L-glutamate in the NRM, but did not antagonize the increase in TFL evoked from the NGCp alpha. These results suggest that the antinociception produced by activation of these bulbospinal pathways is predominantly mediated by spinal delta2 opioid receptors and that there is little, if any, contribution by spinal delta1 opioid receptors.

Topics: Analgesics; Animals; Benzylidene Compounds; Glutamic Acid; Isothiocyanates; Male; Medulla Oblongata; Microinjections; Naltrexone; Narcotic Antagonists; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Spinal Cord

The identification of opioid delta receptor subtypes in mouse brain led to the investigation of the nature of the opioid delta receptors in the mouse isolated vas deferens in vitro. Noncumulative concentration-effect curves were constructed for DPDPE (delta 1 agonist) and [D-Ala2, Glu4]deltorphin (delta 2 agonist) in control tissues, or in tissues which had been incubated with either [D-Ala2, Leu5, Cys6] enkephalin (DALCE) (noncompetitive delta 1 antagonist) or 5'-naltrindole isothiocyanate (5'-NTII) (noncompetitive delta 2 antagonist). Incubation of the tissues with DALCE, under either oxygenated or nonoxygenated conditions, did not alter the concentration-effect curves for either agonist. In contrast, incubation of the tissues with 5'-NTII resulted in a significant rightward displacement of the concentration-effect curves of both DPDPE and [D-Ala2, Glu4] deltorphin. Additionally, naltriben, a selective and competitive delta 2 antagonist, showed no significant difference in its ability to antagonize a fixed, submaximal concentration of either DPDPE or [D-Ala2, Glu4]deltorphin. Furthermore, there was no significant difference in the affinity of naloxone (i.e., pA2) at the receptor(s) acted upon by either DPDPE or [D-Ala2, Glu4]deltorphin. Tolerance to DPDPE or [D-Ala2, Glu4]deltorphin was produced by incubation of the tissues with these agonists; construction of the [D-Ala2, Glu4]deltorphin concentration-effect curve in DPDPE-tolerant tissues demonstrated cross-tolerance between these agonists and, conversely, construction of DPDPE concentration-effect curves in [D-Ala2, Glu4]deltorphin-tolerant tissues revealed cross-tolerance between these agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzylidene Compounds; Drug Tolerance; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; In Vitro Techniques; Isothiocyanates; Male; Mice; Mice, Inbred ICR; Morphinans; Naltrexone; Oligopeptides; Receptors, Opioid, delta; Thiocyanates; Vas Deferens

The possible involvement of delta 2 opioid receptors in the development of morphine dependence was investigated using selective delta 2 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 delta 2 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 delta 2 opioid receptors (by a nonequilibrium and long-lasting antagonist, 5'-NTII) rather than intermittent blockade of delta 2 opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.

Topics: Animals; Enkephalin, Leucine; Isothiocyanates; Male; Mice; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance Withdrawal Syndrome; Thiocyanates

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