Involvement of glycine receptor α1 subunits in cannabinoid-induced analgesia

Lu, Jie-Ping; Fan, Sijia; Zou, Guichang; Hou, Yiwen; Pan, Tao; Guo, Weiwei; Yao, Lei; Du, Feng; Homanics, Gregg E.; Liú, Dan; Zhang, Li; Xiong, Wei

doi:10.1016/j.neuropharm.2018.01.041

Cited by 25 publications

(22 citation statements)

References 63 publications

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“…Our results show that Zymosan A-induced inflammation is associated with an increased expression of spinal α1GlyR subunit in males. This result was in agreement with previously reported data that demonstrated that chronic CFA-induced inflammatory pain correlates with increased α1GlyR subunit expression [17]. The α1GlyR subunit is expressed in mature stages of central neural system development and exerts faster current parameters in comparison with α2 or α3 GlyR [18,19].…”

Section: Discussionsupporting

confidence: 93%

Sex differences in central inflammatory pain sensitization are associated with differential expression of glycine receptors and GLP-1 at the spinal cord

Mariqueo

Amestica

Pino

et al. 2020

Preprint

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BackgroundFemales have higher inflammatory pain representation. However, sex differences in central pain sensitization and the regulation of nociceptive response to peripheral inflammation remain unclear. The central pain sensitization is mediated by inhibitory neurotransmission and glial cell activity dysregulation where spinal glycine and GLP-1 receptors have described play a critical role.ObjectivesThe aim of this study was to compare the mechanical withdrawal nociceptive threshold with spinal glycine receptor subunits and GLP-1 expression in adult male and female rats after inflammatory hypersensitivity.MethodsSex differences in inflammatory nociception were evaluated before and after intraplantar hindpaw Zymosan A injection in Sprague-Dawley rats. Mechanical paw withdrawal thresholds were tested using von Frey filaments.Western blot was used to measure GlyRs subunits protein levels in the spinal cord. GLP-1 was determined using the Magnetic Luminex Assay.ResultsA reduced nociceptive threshold was observed in males and females rats after 4 hours of inflammatory Zymosan A injection. However, this reduction was significantly major in females. Western blot analysis demonstrated significantly increased α1, α2, α3 and β GlyR subunit levels in male rats. Female rats only increased α3 and β GlyR subunits after Zymosan A injection. GLP-1 was reduced in female spinal tissues after an inflammatory injury.ConclusionsOur study indicates that sex differences in nociceptive threshold after inflammatory Zymosan A rat pain sensitization is related to the sex differences in glycine receptor subunits and GLP-1 expression at the spinal cord.

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Section: Discussionsupporting

confidence: 93%

Sex differences in central inflammatory pain sensitization are associated with differential expression of glycine receptors and GLP-1 at the spinal cord

Mariqueo

Amestica

Pino

et al. 2020

Preprint

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“…The amino acid residue S296 in the third transmembrane helix of the α1/α3 GlyR subunits (Figure 5A) has been found to be a critical site for cannabinoid binding 13,15,27 . The S296A mutation of α1/α3 GlyR can significantly reduce the THC‐induced potentiation of I Gly in HEK 293T cells expressing α1/α3 GlyRs carrying S296A mutation (Figure 5B,C).…”

Section: Resultsmentioning

confidence: 97%

Membrane cholesterol dependence of cannabinoid modulation of glycine receptor

Yao

Wells

et al. 2020

The FASEB Journal

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Cannabinoids exert therapeutic effects on several diseases such as chronic pain and startle disease by targeting glycine receptors (GlyRs). Our previous studies have shown that cannabinoids target a serine residue at position 296 in the third transmembrane helix of the α1/α3 GlyR. This site is located on the outside of the ion channel protein at the lipid interface where the cholesterol concentrates. However, whether membrane cholesterol regulates cannabinoid-GlyR interaction remains unknown. Here, we show that GlyRs are closely associated with cholesterol/caveolin-rich domains at subcellular levels. Membrane cholesterol reduction significantly inhibits cannabinoid potentiation of glycine-activated currents in cultured spinal neurons and in HEK 293T cells expressing α1/α3 GlyRs. Such inhibition is fully rescued by cholesterol replenishment in a concentration-dependent manner. Molecular docking calculations further reveal that cholesterol regulates cannabinoid enhancement of GlyR function through both direct and indirect mechanisms. Taken together, these findings suggest that cholesterol is critical for the cannabinoid-GlyR interaction in the cell membrane.

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“…These studies characterized a genetically modified mice carrying a mutation in a1GlyR (i.e., S296A), that render the receptor resistant to DH-CBD. Behavioral studies showed that the DH-CBD-induced analgesia in the CFA model was suppressed in the a1S296A GlyR mice (Lu et al, 2018).…”

Section: Glyrsmentioning

confidence: 99%

“…Interestingly, the analgesic effects of DH-CBD were significantly reduced in a3GlyR knock-out mice (Xiong et al, 2012). However, Lu and co-workers recently reported that a1GlyR is also involved in the DH-CBD-induced analgesia (Lu et al, 2018). These studies characterized a genetically modified mice carrying a mutation in a1GlyR (i.e., S296A), that render the receptor resistant to DH-CBD.…”

Section: Glyrsmentioning

confidence: 99%

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

et al. 2020

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Chronic pain is a common detrimental condition that affects around 20% of the world population. The current drugs to treat chronic pain states, especially neuropathic pain, have a limited clinical efficiency and present significant adverse effects that complicates their regular use. Recent studies have proposed new therapeutic strategies focused on the pharmacological modulation of G-protein-coupled receptors, transporters, enzymes, and ion channels expressed on the nociceptive pathways. The present work intends to summarize recent advances on the pharmacological modulation of pentameric ligandgated ion channels, which plays a key role in pain processing. Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABA A and glycine receptors, reverse chronic painrelated behaviors in preclinical assays. Collectively, these evidences strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans.

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Involvement of glycine receptor α1 subunits in cannabinoid-induced analgesia

Cited by 25 publications

References 63 publications

Sex differences in central inflammatory pain sensitization are associated with differential expression of glycine receptors and GLP-1 at the spinal cord

Sex differences in central inflammatory pain sensitization are associated with differential expression of glycine receptors and GLP-1 at the spinal cord

Membrane cholesterol dependence of cannabinoid modulation of glycine receptor

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

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