THE MU-OPIOID RECEPTOR ANTAGONIST D-PHE-CYS-TYR-D-TRP-ORN-THR-PEN-THR-NH2 (CTOP) [BUT NOT D-PHE-CYS-TYR-D-TRP-ARG-THR-PEN-THR-NH2 (CTAP)] PRODUCES A NONOPIOID RECEPTOR-MEDIATED INCREASE IN K-CERULEUS NEURONS( CONDUCTANCE OF RAT LOCUS)

The somatostatin analogues D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CT OP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) have been used widely as selective antagonists of mu-opioid receptors. Actions of CTO P and CTAP on the membrane properties of rat locus ceruleus neurons we re studied using intracellular recordings oi membrane currents in supe rfused brain slices, CTOP increased a K+ conductance with an EC(50) of 560 nM. The maximal concductance increase produced by CTOP (10 mu M) was similar to that produced by high concentrations of the mu-opioid a gonists D-Ala-Met-enkephalin-glyol (1 mu M) and Met-enkephalin (10 mu M), as well as an alpha(2)-adrenoceptor agonist (UK14304, 3 mu M) and somatostatin (1 mu M). The K+ current produced by CTOP was not antagon ized by naloxone (1 mu M), suggesting it was not mediated by mu-opioid receptors. The K+ currents induced by high concentrations of CTOP des ensitized to 42% of the initial maximum after prolonged superfusion (t (1/2) = 247 sec). In the presence of fully desensitized CTOP responses , somatostatin (1 mu M) still produced near-maximal K+ currents; i.e., there was no cross-desensitization, which suggests that CTOP might ac t on a receptor distinct from somatostatin receptors. However, the con verse did not apply; high concentrations of CTOP (30 mu M) did not pro duce any additional current in the presence of desensitized somatostat in responses. No cross-desensitization was observed between CTOP (10-3 0 mu M) and Met-enkephalin (30 mu M) or nociceptin (3 mu M) regardless of the order of drug application, Cyclo-(7-aminoheptanoyl-Phe-D-Trp-L ys-Thr[Bzl], antagonized both somatostatin- (K-D = 10 mu M) and CTOP- (K-D = 8 mu M) induced K+ currents with similar potency. Concentration s of CTOP (100 nM) that produced a small K+ current partially antagoni zed the actions of Met-enkephalin (10 mu M) on mu-opioid receptors. In contrast to CTOP, CTAP produced no K+ current at concentrations of 30 0 nM and 1 mu M and little current at 10 mu M. CTAP potently antagoniz ed K+ currents produced by the mu-opioid receptor agonist D-Ala-Met-en kephalin-glyol, with an equilibrium dissociation constant of 4 nM (Sch ild analysis), CTAP did not antagonize K+ currents produced by CTOP or somatostatin. These results demonstrate that CTOP is a potent and eff icacious agonist at nonopioid receptors, whereas CTAP is a potent mu-o pioid receptor antagonist with little nonopioid agonist activity in ra t locus ceruleus neurons. The receptor activated by CTOP has yet to be fully resolved but seems to be similar to the somatostatin type 2 rec eptor or perhaps to a receptor closely related to somatostatin or opio id receptors.