Δ9-Tetrahydrocannabinol and Cannabinol Activate Capsaicin-Sensitive Sensory Nerves via a CB1 and CB2 Cannabinoid Receptor-Independent Mechanism

@article{Zygmunt20029TetrahydrocannabinolAC,
  title={$\Delta$9-Tetrahydrocannabinol and Cannabinol Activate Capsaicin-Sensitive Sensory Nerves via a CB1 and CB2 Cannabinoid Receptor-Independent Mechanism},
  author={Peter M. Zygmunt and David A. Andersson and Edward D. H{\"o}gest{\"a}tt},
  journal={The Journal of Neuroscience},
  year={2002},
  volume={22},
  pages={4720 - 4727}
}
Although Δ9-tetrahydrocannabinol (THC) produces analgesia, its effects on nociceptive primary afferents are unknown. These neurons participate not only in pain signaling but also in the local response to tissue injury. Here, we show that THC and cannabinol induce a CB1/CB2 cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves. Other psychotropic cannabinoids cannot mimic this action. The vanilloid receptor antagonist… 
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References

SHOWING 1-10 OF 70 REFERENCES
Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.
Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide
TLDR
It is shown that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP), which indicates that the vanilloid receptor may be another molecular target for endogenousAnandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
Cannabinoid receptors and pain
  • R. Pertwee
  • Biology, Chemistry
    Progress in Neurobiology
  • 2001
Cardiovascular pharmacology of anandamide.
TLDR
The presence of anandamide in endothelial cells, neurones and activated macrophages (monocytes), and its ability to activate CB and vanilloid receptors make this lipid a potential bioregulator in the cardiovascular system.
Induction of vanilloid receptor channel activity by protein kinase C
TLDR
It is shown that activation of protein kinase C (PKC) induces VR1 channel activity at room temperature in the absence of any other agonist, suggesting that PKC may link a range of stimuli to the activation of VRs.
The vanilloid receptor (VR1)‐mediated effects of anandamide are potently enhanced by the cAMP‐dependent protein kinase
TLDR
The ability of AEA to stimulate sensory VR1, with subsequent neuropeptide release, appears to be regulated by the state of activation of PKA, which supports the hypothesis that endogenous AEA might stimulate VR1 under certain pathophysiological conditions.
Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.
TLDR
Most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor, which accounts for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications.
Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition
TLDR
It is shown that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1, a heat-activated ion channel on sensory neurons, and biochemical studies suggest that VR1 associates with this complex.
A capsaicin-receptor homologue with a high threshold for noxious heat
TLDR
It is proposed that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.
Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
TLDR
Results suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues, and (−)‐5′‐DMH‐CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
...
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