Pharmacological selectivity of CTAP in a warm water tail-withdrawal antinociception assay in rats

Rationale To facilitate in vivo characterization of the mu antagonist Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), the present study characterized CTAP selectivity in vivo. Objectives CTAP, the classical antagonist naltrexone, the kappa-selective antagonist nor-binaltorphimine (BNI), and the delta-selective antagonist naltrindole were compared as antagonists of representative mu, kappa, and delta agonists in a warm water tail-withdrawal assay. Materials and methods Male Sprague-Dawley rats were pretreated with CTAP (0.01 to 10.0 mu g, i.c.v.), naltrexone (0.1 to 10 mg/kg s.c.; 0.1 to 10 mu g i.c.v.), nor-BNI (1 mg/kg s.c.), or naltrindole (0.01 to 1 mu g, i.c.v.) and tested with cumulative doses of agonist in 50 or 55 degrees C tail-withdrawal assays. Results At 55 C, morphine and DAMGO produced dose-dependent antinociceptive effects that were antagonized by CTAP or naltrexone (s.c.or i.c.v.) in a surmountable, dose-dependent manner. Neither kappa agonists (bremazocine, spiradoline, U69,593; all s.c.) nor the delta agonist DPDPE (i.c.v.) produced antinociception at 55 degrees C, but all produced full antinociception at 50 degrees C. CTAP did not antagonize effects of spiradoline, U69,593, or DPDPE, whereas nor-BNI produced insurmountable antagonism of effects of kappa agonists, and naltrindole produced surmountable antagonism of effects of DPDPE. Apparent pA(2) estimates for naltrexone, CTAP, and naltrindole agreed with published estimates, although Schild slopes diverged from predictions for simple competitive antagonism. Conclusions CTAP produces dose-dependent antagonism selective for mu-agonist effects in a standard 55 degrees C tail withdrawal antinociceptive assay.