AGONIST AND ANTAGONIST EFFECTS OF DYNORPHIN A-(1-13) IN A THERMAL ANTINOCICEPTION ASSAY IN RHESUS-MONKEYS

The agonist and antagonist effects of intravenously administered dynor phin A-(1- 13) were characterized in the warm water (50 and 55 degrees C) tail withdrawal assay of antinociception in rhesus monkeys. The pe ptide dose-dependently elevated tail withdrawal latencies in 50 degree s C water, but was ineffective in 55 degrees C water. The antinocicept ive effect of dynorphin was surmountably antagonized by quadazocine (0 .1 mg/kg) and nor-binaltorphimine (3.2 mg/kg), but was not antagonized by clocinnamox (0.1 mg/kg); this pattern of antagonism is consistent with a kappa-opioid receptor mediated effect. Pretreatment with dynorp hin A-(1-13) (0.0323.2 mg/kg) antagonized the antinociceptive effects of U50,488 and U69,593 in 55 degrees C water, suggesting a low efficac y action of the peptide at the receptors activated by these kappa agon ists. However, dynorphin A-(1-13) (3.2 mg/kg) did not antagonize other kappa agonists: bremazocine (0.018-0.056 mg/kg) and enadoline (0.0056 -0.018 mg/kg). Taken together, these dynorphin A-(1-13) findings suppo rt the notion of functional kappa-opioid receptor subtypes, and it app ears that dynorphin A-(1 -13) has limited efficacy at one of these sit es. Finally, dynorphin A-(1-13) (0.32 mg/kg) also antagonized the anti nociceptive effects of the mu-agonist etonitazene (0.0018-0.01 mg/kg).