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

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Abstract
1 The effects of methionine5-enkephalin (Met-enkephalin, ME) 5 × 10−8-5 × 10−6 moll−1) were investigated on the resting guinea-pig ileum. 2 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. 3 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 × 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, 10−6moll−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. 4 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. 5 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.