ANTINOCICEPTIVE EFFECTS IN THE FORMALIN AND CAPSAICIN TESTS AFTER INTRATHECAL ADMINISTRATION OF SUBSTANCE-P ANALOGS IN MICE

The antinociceptive effect of substance P- and substance P-(6-11) anal ogues containing D-histidine (D-His) in position 9 was examined in mic e in the formalin and capsaicin tests. [D-Arg1,D-Trp7,9,Leu11]substanc e P (spantide) was used as reference drug. Intrathecal injections of t he [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol re sulted in no significant antinociception as measured in the 2.0% forma lin test, although spantide was antinociceptive in the early and late phases. The early response induced by 0.0625% formalin was reduced sig nificantly by the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol, which were less potent than spantide. The antinociceptio n induced by spantide and a few analogues of substance P and substance P-(6-11) containing D-His was reversed significantly by pretreatment with 2 mg/kg naloxone, an opioid antagonist. The nociceptive response to capsaicin was inhibited significantly by lower doses (2.0 nmol) of the analogues. The antinociception evoked by the analogues was not rev ersed by naloxone in the capsaicin test. Co-injection of the [D-His9]s ubstance P and substance P-(6-11) analogues at 2.0 nmol selectively de creased substance P-induced licking, biting and scratching without aff ecting the behavioural responses to NK2 and NK3 receptor agonists. Spa ntide non-selectively inhibited the behavioural responses produced by not only substance P, but also neurokinin A, D-septide, neurokinin B a nd eledoisin. The data show that the capsaicin test may be a better me thod for evaluating neurokinin antagonists than the formalin test.