Regulation of substance P receptor system in rat striatum by chronic naltrexone treatment

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Chronic blockade of opioid receptors by naltrexone increases opioid peptides in the striatum, and up-regulates brain opioid receptors resulting in functional supersensitivity. Striatal SP content was increased 3.5-fold after 8 days of naltrexone treatment relative to control animals. The present study was undertaken to determine whether SP receptors in the striatum and SP receptor-coupled second messenger system are modulated by increased striatal SP content induced by chronic opioid receptor blockade. The binding affinity and capacity of SP receptors, determined using [ 125I]Bolton-Hunter SP ([ 125I]BHSP) labeled at Lys 3, in striatal synaptosomal membranes were not significantly altered by chronic blockade of opioid receptors. Although the concentrations of [Sar 9,Met (O 2) 11]SP, a NK-1 receptor-specific agonist, and SP(1–7), an aminoterminal major metabolite of SP, required to inhibit half of [ 125I]BHSP binding (IC 50) in striatal synaptosomal membranes were significantly decreased, the IC 50s for SP and an NK-2 receptor-specific agonist, [Nle 10]NK A(4–10), remained unchanged by chronic naltrexone treatment. The data suggest that naltrexone which has no SP receptor antagonistic action, not only indirectly acts on SP-ergic neurons but also causes a change in the apparent affinity of NK-1 receptor (as reflected by changes in IC 50 values) in the striatum. Cellular inositol-1,4,5-trisphosphate [Ins(1,4,5)P 3], quantified by a highly sensitive and selective radioreceptor mass assay, was increased in the striatum by 28% relative to control levels. With [ 3H]Ins(1,4,5)P 3 as a ligand, Scatchard analyses of the concentration-dependent saturation curves showed that the density of striatal intracellular Ins(1,4,5)P 3 receptors was increased by 53%. The levels of SP and cellular Ins(1,4,5)P 3, and the density of Ins(1,4,5)P 3 receptors in the cerebellum, used as a positive control, were unchanged by chronic naltrexone treatment. The findings of opiate antagonist-induced increases in SP striatal content and Ins(1,45)P 3 receptor densities, appear to support the concept of a role of endogenous opioids in the regulation of SP receptor activity. The data also suggest that inter-regulatory mechanisms exist between phospholipase C/phosphoinositide-coupled receptors such as SP receptors, and adenylate cyclase-coupled inhibitory receptors, such as opioid receptors.