The properties of the clonidine withdrawal response of guinea-pig isolated ileum

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Abstract
1 The dependence-inducing effects of clonidine were investigated on the guinea-pig isolated ileum. Clonidine produced relaxation of the ileum with a threshold concentration between 0.01 and 0.1 μmol 1−1. Washout of clonidine did not induce a withdrawal contraction. 2 Following 2 min contact of the ileum with clonidine, 1 μmol 1−1, addition of phentolamine, 5 μmol 1−1, induced a contracture. The phentolamine-precipitated withdrawal contracture did not increase in height with a longer period of contact (32 min) of the ileum with clonidine. 3 The phentolamine-precipitated withdrawal contracture following 2 min contact of ileum with clonidine was abolished by atropine, 5 μmol 1−1, and substance P (SP) antagonists, (D-Pro2, D-Phe7, D-Trp9)-SP and spantide, 10 μmol 1−1. 4 [Met5]enkephalin, 1 μmol 1−1, abolished the withdrawal response to clonidine and clonidine, 1 μmol 1−1, abolished the withdrawal response to [Met5]enkephalin. 5 Following 2 min contact of the ileum with noradrenaline, 5 μmol 1−1, washout or addition of phentolamine or yohimbine, 5 μmol 1−1, also induced a withdrawal response. The noradrenaline washout withdrawal response was abolished by atropine, 5 μmol 1−1, and spantide, 10 μmol 1−1. 6 Since clonidine dependence may be induced as rapidly as opiate dependence in the ileum and the pharmacology of the withdrawal responses is similar, it is suggested that they both induce the same post-receptor neuronal feedback disturbance in which substance P neurones play a major role.