Distribution of Fos-like immunoreactivity in guinea-pig brain following administration of the neurokinin-1 receptor agonist, [SAR9,MET(O2)11]substance P.
The tachykinins are a family of peptides with putative neurotransmitter roles in the nervous system. They mediate their effects via neurokinin-1, neurokinin-2 and neurokinin-3 receptors. There has been increasing interest in the therapeutic application of the tachykinin neurokinin-1 receptor antagonists 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 guinea-pig brain, following intracerebroventricular administration of the neurokinin-1 receptor-selective agonist, [Sar9,Met(O2)11]substance P. The effects of pretreatment with the neurokinin-1 receptor antagonist, SR 140333, were also investigated. Administration of [Sar9,Met(O2)11]substance P induced increased locomotor activity, as well as face washing, grooming and wet-dog shake behaviours, all of which were inhibited by the neurokinin-1 receptor antagonist, SR 140333, indicating the involvement of neurokinin-1 receptors. In order to localize the brain regions activated by [Sar9,Met(O2)11]substance P, the distribution of neurons expressing Fos-like immunoreactivity was examined. [Sar9,Met(O2)11]substance P induced increased Fos-like immunoreactivity in widespread areas, including the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus, periaqueductal gray, area postrema and nucleus of the solitary tract. SR 140333 reduced Fos-like immunoreactivity induced by [Sar9,Met(O2)11]substance P in most areas. Thus, brain regions associated with emotion, sensation, learning and memory, autonomic regulation and emesis were activated by stimulation of neurokinin-1 receptors. The present data have added a functional domain to previous neurokinin-1 receptor 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.
Yip
J
J
Experimental Pharmacology Unit, School of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Newcastle, NSW, Australia.
Chahl
L A
LA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000187:drug effects; D006168:Guinea Pigs; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009928:Organ Specificity; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics*; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists*; D012016:Reference Values; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; C062618:substance P, Sar(9)-Met(O2)(11)-; C085215:SR 140333; D013373:Substance P; D014446:Tyrosine 3-Monooxygenase