u-50488 and 16-methylcyprenorphine

1. Ethylketocyclazocine (EKC) and U50,488H have been employed widely as kappa-receptor agonists in the study of opioid receptor systems. However, the quantification of their agonism in terms of affinities and relative efficacies has not been investigated. 2. In this study, operational model-fitting was used to analyse the effects of irreversible receptor alkylation by beta-chlornaltrexamine (beta-CNA) on the kappa-receptor mediated effects of EKC and U50,488H in the isolated, coaxially stimulated ileum of the guinea-pig. 3. EKC produced monophasic inhibitory concentration-effect curves which were readily amenable to analysis. In contrast U50,488H produced biphasic curves characterized by a higher potency phase of agonism that was susceptible to antagonism by 16-methylcyprenorphine (RX8008M) and a lower potency phase that was apparently non-opioid in nature. 4. Analysis of the kappa-receptor-mediated effects of both agonists indicated that EKC has fifteen fold higher affinity than U50,488H and that the two agonists possess similar intrinsic efficacies.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Binding, Competitive; Cyclazocine; Electric Stimulation; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Male; Models, Biological; Morphinans; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa

The effects of 16-Me cyprenorphine (M80) on the antinociception produced by reexposing rats to a chamber associated with footshock (1 mA, 0.75 sec) 24 hr earlier was assessed with the formalin test. In Experiment 1, intracerebroventricular administration of M80 dose-dependently (0.5-8 micrograms) reversed conditional analgesia. Experiment 2 demonstrated that M80 (5 micrograms) had no effect on baseline pain sensitivity, but completely reversed conditional analgesia. Experiment 3 demonstrated that 0.25 micrograms DAGO, 3.5 micrograms DPDPE, and 28 micrograms U50,488H all produced equivalent levels of antinociception on the formalin test. The 5 micrograms dose of M80 completely reversed the antinociception produced by DPDPE but did not influence that produced by DAGO or U50,488H. These data suggest, that at the doses employed, M80 is a selective delta-opioid receptor antagonist and that delta-receptors are involved in conditional fear-induced analgesia.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Conditioning, Operant; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Fear; Female; Formaldehyde; Injections, Intraventricular; Morphinans; Pain Measurement; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, delta

The effect of the opioid antagonist, 16-methylcyprenorphine (RX8008M), on the antinociceptive action of the mu-selective agonist, morphine, and the kappa-selective agonist, U50488H, has been investigated in the mouse abdominal constriction test. RX8008M produced a dose-dependent antagonism of the antinociceptive effect of morphine, but did not antagonize the response to U50488H. RX8008M should prove a useful probe for the in-vivo characterization of the receptor selectivity of opioid drugs.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; In Vitro Techniques; Male; Mice; Morphinans; Morphine; Muscle Contraction; Narcotic Antagonists; Pyrrolidines