Antinociceptive effects in the formalin and capsaicin tests after intrathecal administration of substance P analogues in mice.

The antinociceptive effect of substance P- and substance P-(6-11) analogues containing D-histidine (D-His) in position 9 was examined in mice in the formalin and capsaicin tests. [D-Arg1,D-Trp7,9,Leu11]substance P (spantide) was used as reference drug. Intrathecal injections of the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol resulted in no significant antinociception as measured in the 2.0% formalin test, although spantide was antinociceptive in the early and late phases. The early response induced by 0.0625% formalin was reduced significantly by the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol, which were less potent than spantide. The antinociception 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 reversed by naloxone in the capsaicin test. Co-injection of the [D-His9]substance P and substance P-(6-11) analogues at 2.0 nmol selectively decreased substance P-induced licking, biting and scratching without affecting the behavioural responses to NK2 and NK3 receptor agonists. Spantide non-selectively inhibited the behavioural responses produced by not only substance P, but also neurokinin A, D-septide, neurokinin B and eledoisin. The data show that the capsaicin test may be a better method for evaluating neurokinin antagonists than the formalin test.