Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent.
This study compared the antinociceptive properties of systemic administration of selective, non-peptidergic antagonists at neurokinin (NK1 and NK2) receptors to those of other classes of antinociceptive agent. (All doses are in mg/kg.) In mice, the NK1 antagonist, CP 99,994, preferentially (inhibitory dose50 (ID50) = 4.4) inhibited the late phase (LP) as compared to the early phase (EP) (16.1) of formalin-induced licking (FIL). A high dose (17.6) elicited ataxia in the rotarod test. Acetic acid-induced writhing was reduced at intermediate doses (10.0) whereas the tail-flick (TF) response to thermal and mechanical stimuli was inhibited only at high doses (22.7 and 17.7, respectively). Modulation of stimulus intensity did not modify the influence of CP 99,994 upon the response to heat. A similar pattern of data was acquired with RP 67,580, although this NK1 antagonist more potently inhibited writhing (2.8). In contrast, RP 68,651, the inactive isomer of RP 67,580, neither reduced the LP of FIL nor modified writhing indicating that these actions of RP 67,580 were stereospecific. Three further NK1 antagonists, 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. Further, SR 140,333 (0.5) and WIN 51,708 (1.4) were potent ligands in the writhing procedure. The NK2 antagonist, SR 48,966, mimicked NK1 antagonists 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 and 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 inhibited all nociceptive responses at doses not provoking ataxia. While the glycine B receptor partial agonist, (+)-HA 966, selectively blocked the LP of FIL and did not evoke ataxia, the NMDA receptor channel blocker, (+)-MK 801, elicited antinociception only at doses close to those provoking ataxia. Finally, the NSAIDs, indomethacin and ibuprofen, the BK2 antagonist, Hoe 140 and the nitric oxide synthase (NOS) inhibitors, 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 did not evoke ataxia and were inactive in the TF procedures.(ABSTRACT TRUNCATED AT 400 WORDS)
Seguin
L
L
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 78290 Croissy-sur-Seine France.
Le Marouille-Girardon
S
S
Millan
M J
MJ
D000595:Amino Acid Sequence; D000700:Analgesics / Q000145:classification / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D005557:Formaldehyde; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013314:Stress, Mechanical; D013696:Temperature
D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2; D005557:Formaldehyde