Distribution of Fos-like immunoreactivity in guinea-pig brain following administration of the neurokinin-1 receptor agonist, [Sar(9),Met(O-2)(11)]substance P

The tachykinins are a family of peptides with putative neurotransmitter rol es in the nervous system. They mediate their effects via neurokinin-1, neur okinin-2 and neurokinin-3 receptors. There has been increasing interest in the therapeutic application of the tachykinin neurokinin-1 receptor antagon ists in the treatment of pain and emesis, and more recently in depression. However, the central role of neurokinin-1 receptors is not well understood. The aims of the present study were to determine the behavioural responses of guinea-pigs, and the distribution of Fos-like immunoreactivity in the gu inea-pig brain, following intracerebroventricular administration of the neu rokinin-1 receptor-selective agonist, [Sar(9),Met(O-2)(11)]substance P. The effects of pretreatment with the neurokinin-1 receptor antagonist, SR 1403 33, were also investigated. Administration of [Sar(9),Met(O-2)(11)]substance P induced increased locomo tor activity, as well as face washing, grooming and wet-dog shake behaviour s, all of which were inhibited by the neurokinin-1 receptor antagonist, SR 140333, indicating the involvement of neurokinin-1 receptors. In order to l ocalize the brain regions activated by [Sar(9),Met(O-2)(11)]substance P, th e distribution of neurons expressing Fos-like immunoreactivity was examined . [Sar(9),Met(O-2)(11)]substance P induced increased Fos-like immunoreactiv ity in widespread areas, including the frontal cortex, hippocampus, amygdal a, thalamus, hypothalamus, periaqueductal gray, area postrema and nucleus o f the solitary tract. SR 140333 reduced Fos-like immunoreactivity induced b y [Sar(9),Met(O-2)(11)]substance P in most areas. Thus, brain regions assoc iated with emotion, sensation, learning and memory, autonomic regulation an d emesis were activated by stimulation of neurokinin-1 receptors. The present data have added a functional domain to previous neurokinin-1 re ceptor localization studies by describing the extensive regions of the CNS that may be activated by stimulation of these receptors, and the potential of neurokinin-1 receptor antagonists to inhibit activation of these regions . (C) 1999 IBRO. Published by Elsevier Science Ltd.