1 The effects of methionine5-enkephalin (Met-enkephalin, ME) 5 x 10 x 5 x 10-6moll-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 mol 1-, were abolished by naloxone, 10-6moll-', added prior to the addition of ME, atropine, 5 x 10-6moll1 and the substance P (SP) antagonist, (D-Pro2, D-Phe7, D-Trp9)-SP, 10-5moI 11 and were reduced by 5-hydroxytryptamine (5-HT)-autodesensitization. Washout contractures following 32 min contact with ME, 10-6mo1l1-, 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. 5It 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.

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The classical tachykinins, substance P, neurokinin A and neurokinin B are predominantly found in the nervous system where they act as neurotransmitters and neuromodulators. Their respective preferred receptors are NK1, NK2, and NK3 receptors. The presence of substance P in nociceptive primary afferent neurons, electrophysiological studies showing that it activated neurons in the dorsal horn of the spinal cord, and behavioral studies in animals, supported the concept that substance P was an important transmitter in the nociceptive pathway. It was therefore surprising that non-peptide NK1 receptor antagonists were ineffective as analgesics in clinical pain conditions. Nevertheless, the discovery that NK1 receptor antagonists had antidepressant activity led to renewed interest in these antagonists. It is disappointing that clinical trials of MK869 (aprepitant) for depression were suspended. The future of NK1 receptor antagonists as antidepressant drugs will depend on the outcome of clinical trials with other NK1 receptor antagonists. NK1 receptor antagonists were also found to be effective antiemetics, and aprepitant has recently become available for the treatment of chemotherapy induced emesis. Although less is known of the potential of NK2 and NK3 receptor antagonists, recent trials of NK3 receptor antagonists have shown efficacy in schizophrenia. The discovery of a new family of tachykinins, the hemokinins and endokinins, which acts on NK1 receptors and has potent effects on immune cells, has implications for the clinical use of NK1 receptor antagonists. Thus specific therapeutic strategies may be required to enable NK1 receptor antagonists to be introduced for treatment of neuropsychiatric disorders.

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1 Schizophrenia is considered to be a neurodevelopmental disorder with origins in the prenatal or neonatal period. Brains from subjects with schizophrenia have enlarged ventricles, reduced cortical thickness (CT) and increased neuronal density in the prefrontal cortex compared with those from normal subjects. Subjects with schizophrenia have reduced pain sensitivity and niacin skin flare responses, suggesting that capsaicin-sensitive primary afferent neurons might be abnormal in schizophrenia. 2 This study tested the hypothesis that intrinsic somatosensory deprivation, induced by neonatal capsaicin treatment, causes changes in the brains of rats similar to those found in schizophrenia. Wistar rats were treated with capsaicin, 50 mg kg À1 subcutaneously, or vehicle (control) at 24-36 h of life. At 5-7 weeks behavioural observations were made, and brains removed, fixed and sectioned. 3 The mean body weight of capsaicin-treated rats was not significantly different from control, but the mean brain weight of male, but not female, rats, was significantly lower than control. 4 Capsaicin-treated rats were hyperactive compared with controls. The hyperactivity was abolished by haloperidol. 5 Coronal brain sections of capsaicin-treated rats had smaller cross-sectional areas, reduced CT, larger ventricles and aqueduct, smaller hippocampal area and reduced corpus callosum thickness, than brain sections from control rats. Neuronal density was increased in several cortical areas and the caudate putamen, but not in the visual cortex. 6 It is concluded that neonatal capsaicin treatment of rats produces brain changes that are similar to those found in brains of subjects with schizophrenia.