No abstract

Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with Ga i/o -type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain Ga i/o isoform, Ga o . However, studies in vivo evaluating morphine-mediated antinociception have not supported these findings. The aim of the present work was to evaluate the contribution of Ga o to MOR-dependent signaling by measuring both antinociceptive and biochemical endpoints in a Ga o null transgenic mouse strain. Male wild-type and Ga o heterozygous null (Ga o + /À) mice were tested for opioid antinociception in the hot plate test or the warm-water tail withdrawal test as measures of supraspinal or spinal antinociception, respectively. Reduction in Ga o levels attenuated the supraspinal antinociception produced by morphine, methadone, and nalbuphine, with the magnitude of suppression dependent on agonist efficacy. This was explained by a reduction in both high-affinity MOR expression and MOR agoniststimulated G protein activation in whole brain homogenates from Ga o + /À and Ga o homozygous null (Ga o À/À) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between Ga o + /À and wild-type mice and high-affinity MOR expression was unchanged in spinal cord tissue. However, the action of the partial agonist nalbuphine was compromised, showing that reduction in Ga o protein does decrease spinal antinociception, but suggesting a higher Ga o protein reserve. These results provide the first in vivo evidence that Ga o contributes to maximally efficient MOR signaling and antinociception.

No abstract

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 μ-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 Gαo protein, GαoG184S (Gαo RGSi), was evaluated for morphine or methadone antinociception in response to noxious thermal stimuli. Mice expressing Gαo 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 Gαo RGSi subunits, there was a small loss of Gαo 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.

Parkinson's disease (PD) is the second most common neurodegenerative disease and is typically associated with progressive motor dysfunction, although PD patients also exhibit a variety of non-motor symptoms. The neuropathological hallmark of PD is intraneuronal inclusions containing primarily α-Synuclein (α-Syn), and several lines of evidence point to α-Syn as a key contributor to disease progression. Thus, basic research in the field of PD is largely focused on understanding the pathogenic properties of α-Syn. Over the past 2 y, these studies helped to identify several novel therapeutic strategies that have the potential to slow PD progression; such strategies include sequestration of extracellular α-Syn through immunotherapy, reduction of α-Syn multimerization or intracellular toxicity, and attenuation of the neuroinflammatory response. This review describes these and other putative therapeutic strategies, together with the basic science research that led to their identification. The current breadth of novel targets for the treatment of PD warrants cautious optimism in the fight against this devastating disease.