PubMed · 7738532
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J C Kruse. 1995. Pain control.. https://pubmed.ncbi.nlm.nih.gov/7738532/
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Despite much study since its discovery in 1995, the effects of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the 'orphan' opioid receptor, on nociceptive sensitivity remain unclear. Different laboratories have variously reported hyperalgesic, analgesic, anti-analgesic or no effect of the peptide on thermal assays following supraspinal injection in rodents. We and others have argued previously that methodological inconsistencies and experimental parameters may explain some of the contradictions in the literature, especially in mice where intracerebroventricular (i.c.v.) injections proceed directly through the skull. We report presently that both the magnitude of stress-induced analgesia (SIA) produced by such i.c.v. injections, and the ability of OFQ/N to antagonize this opioid-mediated SIA, are strain-dependent. Specifically, significant injection-related SIA was observed in four of six strains studied (outbred: CD-1, SW; inbred: AKR/J, BALB/cJ, C3H/HeJ, CBA/J) on the 47.5 degrees C tail-withdrawal assay, and OFQ/N blocked this SIA in two strains. These data suggest that genetic variability among subject populations may underlie the inconsistent findings among researchers, and may in addition provide a promising avenue for future study of this novel neuromodulator.
Members of the muscarinic acetylcholine receptor family (M1-M5) are known to be involved in a great number of important central and peripheral physiological and pathophysiological processes. Because of the overlapping expression patterns of the M1-M5 muscarinic receptor subtypes and the lack of ligands endowed with sufficient subtype selectivity, the precise physiological functions of the individual receptor subtypes remain to be elucidated. To explore the physiological roles of the M2 muscarinic receptor, we have generated mice lacking functional M2 receptors by using targeted mutagenesis in mouse embryonic stem cells. The resulting mutant mice were analyzed in several behavioral and pharmacologic tests. These studies showed that the M2 muscarinic receptor subtype, besides its well documented involvement in the regulation of heart rate, plays a key role in mediating muscarinic receptor-dependent movement and temperature control as well as antinociceptive responses, three of the most prominent central muscarinic effects. These results offer a rational basis for the development of novel muscarinic drugs.