naltrindole-5--isothiocyanate and 7-benzylidenenaltrexone

A large body of evidence suggests an important role of delta-opioid receptor agonists in antinociception at the level of the spinal cord. Our study was undertaken to analyse the spinal antinociceptive and antiallodynic effects of delta(1)- and delta(2)-opioid receptor agonists and antagonist after their acute and chronic intrathecal administration in a neuropathic pain model in the rat. In rats with a crushed sciatic nerve, the delta(1)-opioid receptor agonist [D-Pen(2), D-Pen(5)]enkephalin (DPDPE, 5-25 microg i.t.) and the delta(2)-opioid receptor agonist deltorphin II (1.5-25 microg i.t.) dose dependently antagonized the cold-water allodynia which developed after sciatic nerve injury. These effects of DPDPE were antagonized by 7-benzylidenenaltrexon (BNTX, 1 microg i.t.) while the effects of deltorphin II were antagonized by 5'naltrindole izotiocyanate (5'NTII, 25 microg i.t.). Both agonists had a dose-dependent, statistically significant effect on the tail-flick latency in two tests, with focused light and cold water. Chronic administration of DPDPE (25 microg i.t.) and deltorphin II (15 microg i.t.) resulted in significant prolongation of the reaction time determined on days 2, 4 and 6 post-injury. In conclusion, our results show an antiallodynic and antinociceptive action of DPDPE and deltorphin II at the spinal cord level, which suggests that both delta-opioid receptor subtypes play a similar role in neuropathic pain. This indicates that not only delta(1)- but also delta(2)-opioid receptor agonists can be regarded as potential drugs for the therapy of neuropathic pain.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Benzylidene Compounds; Dose-Response Relationship, Drug; Enkephalin, D-Penicillamine (2,5)-; Isothiocyanates; Male; Naltrexone; Narcotic Antagonists; Neuralgia; Oligopeptides; Pain Measurement; Protein Isoforms; Rats; Rats, Wistar; Receptors, Opioid, delta; Sciatic Nerve; Time Factors

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