| First Author | Lamberts JT | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 10 | Pages | 4369-77 |
| PubMed ID | 23467353 | Mgi Jnum | J:196283 |
| Mgi Id | MGI:5487688 | Doi | 10.1523/JNEUROSCI.5470-12.2013 |
| Citation | Lamberts JT, et al. (2013) Differential control of opioid antinociception to thermal stimuli in a knock-in mouse expressing regulator of G-protein signaling-insensitive Galphao protein. J Neurosci 33(10):4369-77 |
| abstractText | Regulator of G-protein signaling (RGS) proteins classically function as negative modulators of G-protein-coupled receptor signaling. In vitro, RGS proteins have been shown to inhibit signaling by agonists at the mu-opioid receptor, including morphine. The goal of the present study was to evaluate the contribution of endogenous RGS proteins to the antinociceptive effects of morphine and other opioid agonists. To do this, a knock-in mouse that expresses an RGS-insensitive (RGSi) mutant Galphao protein, Galphao(G184S) (Galphao RGSi), was evaluated for morphine or methadone antinociception in response to noxious thermal stimuli. Mice expressing Galphao RGSi subunits exhibited a naltrexone-sensitive enhancement of baseline latency in both the hot-plate and warm-water tail-withdrawal tests. In the hot-plate test, a measure of supraspinal nociception, morphine antinociception was increased, and this was associated with an increased ability of opioids to inhibit presynaptic GABA neurotransmission in the periaqueductal gray. In contrast, antinociception produced by either morphine or methadone was reduced in the tail-withdrawal test, a measure of spinal nociception. In whole-brain and spinal cord homogenates from mice expressing Galphao RGSi subunits, there was a small loss of Galphao expression and an accompanying decrease in basal G-protein activity. Our results strongly support a role for RGS proteins as negative regulators of opioid supraspinal antinociception and also reveal a potential novel function of RGS proteins as positive regulators of opioid spinal antinociceptive pathways. |
