ANTINOCICEPTIVE PROFILES OF NON-PEPTIDERGIC NEUROKININ(1) AND NEUROKININ(2) RECEPTOR ANTAGONISTS - A COMPARISON TO OTHER CLASSES OF ANTINOCICEPTIVE AGENT

This study compared the antinociceptive properties of systemic adminis tration of selective, nonpeptidergic antagonists at neurokinin (NK1 an d NK2) receptors to those of other classes of antinociceptive agent. ( All doses are in mg/kg.) In mice, the NK1 antagonist, CP 99,994, prefe rentially (inhibitory dose(50) (ID50) = 4.4) inhibited the late phase (LP) as compared to the early phase (EP) (16.1) of formalin-induced li cking (FIL). A high dose (17.6) elicited ataxia in the rotarod test. A cetic acid-induced writhing was reduced at intermediate doses (10.0) w hereas the tail-flick (TF) response to thermal and mechanical stimuli was inhibited only at high doses (22.7 and 17.7, respectively). Modula tion of stimulus intensity did not modify the influence of CP 99,994 u pon the response to heat. A similar pattern of data was acquired with RP 67,580, although this NK1 antagonist more potently inhibited writhi ng (2.8). In contrast, RP 68,651, the inactive isomer of RP 67,580, ne ither reduced the LP of FIL nor modified writhing indicating that thes e actions of RP 67,580 were stereospecific. Three further NK1 antagoni sts, SR 140,333, WIN 51,708 and WIN 62,577, likewise inhibited the LP of FIL and failed to modify the TF response at non-ataxic doses. Furth er, SR 140,333 (0.5) and WIN 51,708 (1.4) were potent ligands in the w rithing procedure. The NK2 antagonist, SR 48,966, mimicked NK1 antagon ists in preferentially inhibiting the LP (7.7) as compared to the EP ( 26.9) of FIL. Further, only at doses higher than those evoking ataxia (20.9), did SR 48,968 modify the TF response (36.5 and 32.0 for heat a nd pressure, respectively). However, it differed to NK1 antagonists in being inactive in the writhing test (> 40.0). In comparison to these NK1 and NK2 antagonists, the mu-opioid agonists (morphine and fentanyl ) and kappa-opioid agonists (enadoline and U 69,593) equipotently inhi bited all nociceptive responses at doses not provoking ataxia. While t he glycine B receptor partial agonist, (+)-HA 966, selectively blocked the LP of FIL and did not evoke ataxia, the NMDA receptor channel blo cker, (+)-MK 801, elicited antinociception only at doses close to thos e provoking ataxia. Finally, the NSAIDs, indomethacin and ibuprofen, t he BK2 antagonist, Hoe 140 and the nitric oxide synthase (NOS) inhibit ors, L-NAME and 7 nitroindazole, inhibited the LP (but not the EP) of FIL and (except for L-NAME) also reduced writhing: in contrast, they d id not evoke ataxia and were inactive in the TF procedures. In conclus ion, NK1 and NK2 receptor antagonists exert their antinociceptive acti vity preferentially against prolonged, chemical noxious stimuli: these actions are expressed at doses lower than those eliciting disruption of motor behaviour. In distinction, irrespective of stimulus intensity , they display little activity against phasic thermal and mechanical s timuli. These profiles of antinociceptive activity may be clearly dist inguished from those of mu- and kappa-opioids but resemble those of ce rtain other drug classes.