(255) Effects of Cannabinoids on Responses of Human Dorsal Root Ganglia Neurons

Davidson, Steve; Ford, Zachary K.; Chen, S.

doi:10.1016/j.jpain.2019.01.177

Cited by 1 publication

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“…Consistent with this body of work, our calcium imaging results indicate that CB-13 reduces PGE2-induced TRPV1 sensitization in mouse DRG neurons (Figure 4). Interestingly, one recent abstract reported no effect of CB-13 on PGE2-induced TRPV1 sensitization in human sensory neurons [15]. The apparent discrepancy may be due to biological differences across species between mouse DRG and human and rat DRG, such as the lack of G protein-coupled inwardly rectifying potassium channels in mouse DRG neurons [56].…”

Section: Discussionmentioning

confidence: 99%

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

Jiang

et al. 2021

Preprint

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Activation of cannabinoid receptor type 1 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1 receptors is accompanied by unwanted side effects, such as tolerance and dependence. Efforts to develop novel analgesics have focused on targeting peripheral CB1 receptors to circumvent central CB1-related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB1-preferring agonist CB-13 on nociception and central CB1-related phenotypes in an inflammatory model of pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion (DRG) neurons. CB-13 reduced inflammation-induced mechanical allodynia in a peripheral CB1 receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse DRG neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E2, providing potential mechanistic explanations for the analgesic actions of peripheral CB1 receptor activation. With acute dosing, phenotypes associated with central CB1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB1 receptor dependence, even at a dose that did not produce central CB1 receptor-mediated phenotypes on acute dosing. This suggests repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.

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Section: Discussionmentioning

confidence: 99%

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

Jiang

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

(255) Effects of Cannabinoids on Responses of Human Dorsal Root Ganglia Neurons

Cited by 1 publication

References 0 publications

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of CNS activity with repeated dosing

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