Substance P induces a cardiovascular defense reaction in the rat: pharmacological characterization.

Abstract

In this study in conscious rats, we tested the hypothesis that substance P, a central pressor peptide and a potential transmitter substance of pain pathways, could be involved in the cardiovascular defense reaction that is typically associated with unpleasant sensory stimuli. The hemodynamic responses to centrally administered substance P were pharmacologically characterized. The increases in blood pressure and heart rate after intracerebroventricular injections of substance P were accompanied by mesenteric and renal vasoconstriction and hind limb vasodilation (pulsed-Doppler flow probes). The pressor and vasoconstrictor responses were attenuated by peripheral alpha 1-adrenoceptor blockade with prazosin but were not influenced by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me) arginine vasopressin (AVP). Cardiac beta 1-adrenoceptor blockade with metoprolol abolished the tachycardic and reduced the pressor responses. Substance P-induced hind limb vasodilation was not sensitive to intravenous atropine but was largely prevented by peripheral beta 2-adrenoceptor blockade with ICI 118,551. Thus, the substance P-induced pressor effects are mediated by alpha 1-adrenergic sympathetic vasoconstriction and beta 1-adrenergic cardiac stimulation, whereas the hind limb vasodilation is mainly due to beta 2-adrenergic stimulation. Substance P dose-dependently (0.01-10 micrograms i.c.v.) released oxytocin but not vasopressin or adrenocorticotropic hormone (ACTH) from the pituitary gland. High doses reduced basal ACTH levels. Together with the hemodynamic responses, a behavioral arousal reaction was observed, which included increased locomotion, grooming, scratching, and skin biting. Our results demonstrate that a neuropeptide can induce classic cardiovascular defense reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of selective antagonists to dissociate the central cardiovascular and behavioural effects of tachykinins on NK1 and NK2 receptors in the rat

“…These behavioural responses are compatible with the reaction of rodents to nociceptive stimuli (Unger et al, 1988). Similar cardiovascular responses can be induced by microinjections of SP into distinct hypothalamic areas suggesting that hypothalamic tachykinin receptors may mediate the central cardiovascular and behavioural effects observed after i.c.v.…”

Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression

“…First, SP has direct actions in brain regions that orchestrate stress responses, such as the amygdala and hypothalamus (Boyce et al, 2001;Culman and Unger, 1995;Shaikh et al, 1993;Smith et al, 1999;Unger et al, 1988). It is likely that known antidepressants act through a final common pathway that includes the action of SP at the NK 1 receptor.…”

“…SP displays highest affinity for tachykinin, type 1 [NK 1 ] receptors (Otsuka and Yoshioka, 1993). It has long been considered to be a specialized sensory transmitter, which is released when an organism is exposed to noxious stimuli (Lim, 1966;Maggi, 1995) and that seems to synchronize physiologic 'survival-type' (stress) responses such as might occur upon noxious stimulation (Boyce et al, 2001;Culman and Unger, 1995;Shaikh et al, 1993;Smith et al, 1999;Unger et al, 1988. ) We thus speculated that in the absence of actual trauma or noxious stimuli, excessive SP activity in key limbic circuits might spawn a cascade of psychophysiological activity, producing signs and symptoms such as those observed in anxiety or depression.…”

Substance P in the medial amygdala: Emotional stress-sensitive release and modulation of anxiety-related behavior in rats

“…T he neuropeptide substance P (SP) and its preferred neurokinin-1 (NK 1 ) receptor have been proposed as possible targets for new antidepressant and anxiolytic therapies. Several preclinical studies have demonstrated a range of anxiety-related behaviors and defensive cardiovascular changes in response to central administration of SP agonists (1)(2)(3)(4)(5)(6).…”