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 μg, i.c.v.), naltrexone (0.1 to 10 mg/kg s.c.; 0.1 to 10 μg i.c.v.), nor-BNI (1 mg/kg s.c.), or naltrindole (0.01 to 1 μg, i.c.v.) and tested with cumulative doses of agonist in 50 or 55°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°C, but all produced full antinociception at 50°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°C tail withdrawal antinociceptive assay.
- CTAP selective drug antagonism
- Opioid analgesics