naltrindole-5--isothiocyanate and naltrindole

Although the interactions between the mu- and the delta-opiate receptor subtypes are well documented with regard to supraspinal analgesia, less is known about the mutual interactions on respiratory depression. To clarify the functional interactions between both opiate receptor subtypes with regard to antinociception and respiratory depression, male Wistar rats were intravenously injected with 2.5 microg/kg of the mu-opiate agonist sufentanil and subsequently intravenously challenged with the delta antagonist naltrindole (NTI) or naltrindole 5'-isothiocyanate (5'-NTII), a delta-2 antagonist. Antinociception was measured by means of the tail-flick latency, and respiratory depression was evaluated by means of analysis of PaCO2, PaO2, and oxygen saturation. To quantify the antagonistic properties of NTI and 5'-NTII, mean areas under the curve were calculated for groups treated with sufentanil, control vehicle, and sufentanil plus a dose of the antagonists. NTI, but not 5'-NTII, antagonized the sufentanil-induced antinociception at 10 mg/kg NTI. Below this dose the effects were inconsistent. The sufentanil-induced hypercapnia and hypoxia were diminished with 10 mg/kg NTI or 5'-NTII. These data indicate that NTI antagonizes the sufentanil-induced antinociception and respiratory depression in rats. A dissociation between the antinociception and respiratory depression following intravenous sufentanil could be obtained with 10 mg/kg 5'-NTII pointing to different regulatory effects of opiate delta receptor subtypes on mu-opiate agonist-induced behavioral effects.

Topics: Analgesics, Opioid; Animals; Depression, Chemical; Hydrogen-Ion Concentration; Hypercapnia; Hypoxia; Isothiocyanates; Male; Naltrexone; Narcotic Antagonists; Pain Measurement; Rats; Rats, Wistar; Reaction Time; Receptors, Opioid, mu; Respiration; Sufentanil

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