EFFECT OF LONGITUDINAL MUSCLE MYENTERIC PLEXUS REMOVAL AND INDOMETHACIN ON THE RESPONSE TO TACHYKININ NK-2 AND NK-3 RECEPTOR AGONISTS IN THE CIRCULAR MUSCLE OF THE GUINEA-PIG ILEUM

1 The effect of removal of the longitudinal muscle-myenteric plexus (L M-MP) and/or indomethacin (10 mu M) on the response to the tachykinin NK-2 receptor selective agonist, [beta Ala(8)]NKA(4-10), or to the NK- 3 receptor selective agonist, senktide, was investigated by measuring mechanical activity (isotonic recording) of circular muscle (ring prep aration) of the guinea-pig ileum. 2 Indomethacin (10 mu M) increased t he percentage of ileal rings displaying spontaneous activity, either i ntact or LM-MP-free. The response to senktide (10nM and 1 mu M) was lo wer in LM-MP-free than in intact ileal rings,either in the absence or presence of indomethacin. The response to a low concentration (10nM) o f [beta Ala(8)] NKA(4-10) was enhanced in LM-MP-free rings and by indo methacin. 3 In intact ileal rings, the response to senktide was unaffe cted by atropine (3 mu M) alone or by the tachykinin NK-2 receptor ant agonist MEN 10,376 (10 mu M) alone while it was reduced by the combine d administration of the two antagonists. The response to senktide was greatly reduced by tetrodotoxin (TTX, 1 mu M). Senktide-induced contra ctions (10nM) were also reduced by the blocker of N-type voltage-sensi tive calcium channels, omega-conotoxin (CTX, 0.1 mu M). 4 In about 30% of preparations tested, an inhibitory response (decrease in spontaneo us activity) to 10nM senktide, was disclosed in CTX-treated intact ile al rings. This inhibitory effect was TTX-sensitive. 5 In LM-MP-free il eal rings, the response to senktide was abolished or reduced by atropi ne and MEN 10,376, alone or in combination, and was also reduced or ab olished by TTX and CTX. 6 The response to [beta Ala(8)]NKA (4-10) was inhibited by MEN 10,376, in both intact and LM-MP-free ileal rings whi le it was unaffected by atropine, TTX or CTX. 7 These results indicate that indomethacin pretreatment induces a regular background activity for studying the motor response to tachykinins in the circular muscle of the ileum, probably by blocking the formation of relaxant prostanoi ds. A further increase in sensitivity to direct smooth muscle stimulat ion (NK-2 receptor agonist) can be obtained by removal of the LM-MP. T he response to NK-3 receptor stimulation is diminished but not abolish ed by removal of the LM-MP, suggesting that NK-3 receptors are located on neuronal bodies of myenteric neurons, but possibly also at other s ites (possibly, nerve terminals). Furthermore, the presence of NK-3 re ceptors on myenteric plexus neurons, which inhibit circular muscle act ivity, is suggested.