[DES-TYR(1)]DYNORPHIN A-(2-17) HAS NALOXONE-INSENSITIVE ANTINOCICEPTIVE EFFECT IN THE WRITHING ASSAY

The dynorphin family of peptides stands out among the opioids in that its members are not antinociceptive after central administration in th e common antinociceptive assays. In addition, reports of spinal antino ciception have been conflicting. We have tested the antinociceptive ac tivity of i.v. dynorphin A-(1-13) in the writhing assay and have found it to be very potent, with an ED(50) of 1.0 (0.99-1.02) mu mol/kg. Re markably, [des-tyr(1)]dyn A-(2-17) was equally active with an ED(50) o f 1.1 (0.99-1.20). This activity was also retained by several smaller, non-opioid dynorphin A fragments and was not affected by the presence of either 50 mu mol/kg naloxone or 20 mu mol/kg Nor-BNI. Further, ED( 50) values were not different in morphine-dependent mice. The peak eff ect of dyn A-(1-13) and A-(2-17) was observed 5 min after administrati on and the effect of dyn A-(1-13) or dyn A-(2-17) was still measurable 1 hr after i.v. administration with a 5- to 6-fold increase in ED(50) at this time. The ED(50) values after i.c.v. and i.t. administration of dyn A-(1-13) were similar to those reported previously. Dyn A(2-17) was also effective by these routes with ED(50) values not significant ly different from those of dyn A-(1-13), Both dyn A-(1-13) and A-(2-17 ) were also active when injected i.p., whereas ED(50) values increased substantially after s.c. administration. Of numerous other ligands te sted for antinociceptive activity in our writhing assay, two had subst antial efficacy, LY235959, a glutamate antagonist with an ED(50) of 3. 3 (2.4-4.6) mu mol/kg, and PKB 4202, a bradykinin B-2 antagonist with an ED(50) of 6.4 (6.2-6.6) mu mol/kg. The writhing assay is recognized as a nonspecific test of peripheral antinociception in which numerous and diverse painkillers are active. Consequently, we further tested t he ability of selected compounds for their ability to suppress the exp ression of withdrawal in morphine-dependent animals, a novel action of dynorphin. Neither LY235959 nor PKB 4202 significantly affected the n aloxone ED(50) to precipitate withdrawal jumping in morphine-dependent mice. These data suggest a unique, non-opioid role for dynorphin pept ides as potential analgesics and modulators of the opioid system.