SR142801 behaves as a tachykinin NK-3 receptor agonist on a spinal nociceptive reflex in the rat

Effects of two commonly used tachykinin NK-3 receptor antagonists (SR 14280 1 and R820) intrathecally (i.t.) administered were assessed in the rat tail -flick test. SR142801 and its (R)-enantiomer SR142806 (1.3, 6.5 and 65 nmol ) were found as potent as senktide and [MePhe(7)]NKB (NK-3 selective agonis ts) to induce transient antinociceptive effects. Naloxone(10 Gig) and R820 (6.5 nmol) blocked reversibly the responses to 6.5 nmol senktide, [MePhe(7) ]NKB, SR142801 and SR142806 when administered i.t. 15 min earlier. However, the antinociceptive responses induced by SR142801 and SR142806 were not af fected by i.t. pretreatments with NK-1 (6.5 nmol SR140333) and NK-2 (6.5 nm ol SR48968) receptor antagonists. In control experiments, the NK-1 and NK-2 antagonists prevented the hyperalgesic effects to NK-I ([Sar(9),Met(O-2)(1 1)]SP) and NK-2 ([beta-Ala(8)] NKA(4-10)) receptor agonists (6.5 nmol i.t.) , respectively. R820 had no direct effect on nociceptive threshold and fail ed to alter angiotensin II-induced antinociception The data suggest that th e antinociceptive effect of SR142801 is due to an agonist effect at NK-3 re ceptor in the rat spinal cord that involves a local opioid mechanism. These results can be best explained by the existence of inter-species NK-3 recep tor subtypes.