Contracture of guinea-pig ileum on withdrawal of methionine5-enkephalin is mediated by substance P.

The effects of methionine5-enkephalin (Met-enkephalin, ME) 5 X 10(-8)-5 X 10(-6) moll-1) were investigated on the resting guinea-pig ileum. While in contact with the ileum, ME reduced the natural tone and movements, but following washout a contracture occurred which increased with increasing duration of the contact period from 0.5 to 32 min and with increasing concentration of the ME present during the contact period. The washout contractures after 2 min contact with ME, 10(-6) moll-1, were abolished by naloxone, 10(-6)moll-1, added prior to the addition of ME, atropine, 5 X 10(-6)moll-1 and the substance P (SP) antagonist, (D-Pro2, D-Phe7, D-Trp9)-SP, 10(-5)moll-1 and were reduced by 5-hydroxytryptamine (5-HT)-autodesensitization. Washout contractures following 32 min contact with ME, 10(-6)moll-1, were significantly inhibited by the SP antagonist and naloxone and were abolished by a combination of atropine and the SP antagonist, but were not significantly reduced by atropine alone or by 5-HT-desensitization. Contractures of ileum occurred on addition of naloxone to ileal segments exposed to ME for 2 or 32 min. These contractures were also inhibited by the SP antagonist but a combination of atropine and SP-desensitization was required to abolish them. It was concluded that gut dependence occurs following very brief exposure to an opioid and that SP plays a central role in the withdrawal response precipitated either by washout or addition of naloxone.