Regulation of substance P receptor system in rat striatum by chronic naltrexone treatment.
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 Lys3, in striatal synaptosomal membranes were not significantly altered by chronic blockade of opioid receptors. Although the concentrations of [Sar9,Met (O2)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 (IC50) in striatal synaptosomal membranes were significantly decreased, the IC50s for SP and an NK-2 receptor-specific agonist, [Nle10]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 IC50 values) in the striatum. Cellular inositol-1,4,5-trisphosphate [Ins(1,4,5)P3], 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)P3 as a ligand, Scatchard analyses of the concentration-dependent saturation curves showed that the density of striatal intracellular Ins(1,4,5)P3 receptors was increased by 53%. The levels of SP and cellular Ins(1,4,5)P3, and the density of Ins(1,4,5)P3 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(1,4,5)P3 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.
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Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City 64108-2792.
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007457:Iodine Radioisotopes; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage*; D009292:Narcotic Antagonists; D010716:Phosphatidylinositols / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects*; D013373:Substance P / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007457:Iodine Radioisotopes; D009292:Narcotic Antagonists; D010716:Phosphatidylinositols; D018160:Receptors, Cytoplasmic and Nuclear; D018040:Receptors, Neurokinin-1; D013373:Substance P; D009271:Naltrexone; D015544:Inositol 1,4,5-Trisphosphate