sr140333b and Disease-Models--Animal

Substance P (SP) is a neuropeptide that can modulate inflammatory mediator release through activation of NK(1) receptors (NK(1)R). Some studies have also suggested the involvement of SP in lipopolysaccharide (LPS)-induced fever. However, the precise contribution of this neuropeptide to the pathways activated during fever is unknown. In this study we investigated the effect of a selective NK(1)R antagonist, SR140333B, on the febrile response induced by LPS and cytokines. Our results show that the systemic injection of SR140333B did not modify the fever induced by LPS at a dose that is able to reduce protein extravasation induced by SP in the skin. On the other hand, intracerebroventricular administration of SR140333B significantly reduced the fever induced by peripheral injection of LPS. These data emphasize an important role for SP in the central nervous system during the febrile response to LPS, and are reinforced by the fact that intracerebroventricular injection of SP also induced fever in a dose-dependent manner in captopril-treated rats. Considering that the febrile response can result from the generation of several endogenous pyrogens, among them interleukin (IL)-1β and macrophage inflammatory protein-1α (CCL3/MIP-1α), we also examined the effect of SR140333B on the fever induced by these cytokines which act through prostaglandin-dependent and -independent mechanisms, respectively. Surprisingly, SR140333B did not modify the febrile response to IL-1β or CCL3/MIP-1α. Altogether these data suggest that the central action of SP is essential for LPS-, but not for IL-1β- or CCL3/MIP-1α-induced fever.

Topics: Animals; Body Temperature; Central Nervous System; Chemokine CCL3; Disease Models, Animal; Dose-Response Relationship, Drug; Fever; Injections, Intraventricular; Interleukin-1beta; Lipopolysaccharides; Male; Neurokinin-1 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Neurokinin-1; Time Factors; Tropanes

Substance P is an important neurotransmitter or neuromodulator in central nervous system. Morphological studies have revealed the existence of substance P and its high affinity receptor, neurokinin-1 receptor, in globus pallidus. The expression of neurokinin-1 receptor in external globus pallidus has been reported to be decreased or unchanged in parkinsonian patients. To further investigate the effects of pallidal neurokinin-1 receptor in Parkinson's disease, an in vivo extracellular recording in 6-hydroxydopamine parkinsonian rats was performed. Micro-pressure ejection of selective neurokinin-1 receptor agonist, [Sar9,Met(O2)11] substance P (0.1mM), increased the spontaneous firing rate of pallidal neurons by 9.1% on the lesioned side, which was significantly weaker than that on the unlesioned side (20.7%), and that in normal rats (30.0%). The selective neurokinin-1 receptor antagonist, SR140333B, prevented the excitatory effects induced by [Sar9,Met(O2)11] substance P. Based on the action of substance P in globus pallidus of parkinsonian rats we hypothesize that the activity of neurokinin-1 receptors in globus pallidus may be decreased under parkinsonian state. This finding may provide a rationale for further investigations into the potential of pallidal substance P system in the treatment of Parkinson's disease.

Topics: Action Potentials; Adrenergic Agents; Analysis of Variance; Animals; Behavior, Animal; Compulsive Behavior; Disease Models, Animal; Drug Interactions; Globus Pallidus; Male; Medial Forebrain Bundle; Neurons; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Wistar; Substance P; Tropanes