Non‐psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action

Abstract

BACKGROUND AND PURPOSETwo non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception. EXPERIMENTAL APPROACHElectrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey. KEY RESULTSCannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB1 adenosine A1 and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD. CONCLUSIONS AND IMPLICATIONSCBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action. BJP

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

“…ON cell facilitation may be sufficiently effective that a reduction in ON cell activity alone is antinociceptive. Indeed, supraspinal administration of several nonopioid compounds suppresses evoked ON cell bursts (while depressing the spontaneous discharge of ON and OFF cells) and increases tail flick latency in anesthetized rats (de Novellis et al, 2008(de Novellis et al, , 2012Maione et al, 2011). As withdrawal magnitudes were not measured in these studies, it is unclear whether magnitudes were decreased.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…Conversely, the action of CBD upon TRPV1 does not seem to regulate the descending pathway of antinociception. It appears that the reduction spikes frequency in both ON cells and OFF cells in the RVM caused by CBD is not reversed with 5′-iodo-resiniferatoxin, which antagonises TRPV1 [250]. On the contrary, it appears that the mechanism of action of CBD upon this descending pathway of antinociception may be mediated by TRPA1 [250].…”

“…It appears that the reduction spikes frequency in both ON cells and OFF cells in the RVM caused by CBD is not reversed with 5′-iodo-resiniferatoxin, which antagonises TRPV1 [250]. On the contrary, it appears that the mechanism of action of CBD upon this descending pathway of antinociception may be mediated by TRPA1 [250]. Finally, although the inhibition of TRPM8 does not seem to be involved in the alleviation of inflammatory and neuropathic pain [255], it does appear that it attenuates cold hyperalgesia and tactile allodynia [253].…”

“…It has been shown that a per os administration of CBD exerts antihyperalgesic effects on rat models of neuropathic and inflammatory pain [248,249]. Microinjections of 3 nM CBD in the ventrolateral periaqueductal gray appears to reduce the frequency of spikes generated by both ON cells and OFF cells (localized in the rostral ventromedial medulla (RVM), controlling the descending pathway of antinociception [250]. Furthermore, CBD appears to control allodynia and neuropathic pain caused by paclitaxel in mice [251,252].…”

“…Therefore, it is not known whether the effect of CBD upon this protein is relevant to treat pain. CB 1 R represent a useful target in the treatment of pain, although both the alleged antagonistic profile of CBD at CB 1 R at supraphysiological concentrations in vitro and absence of CB 1 R-mediated effects in vivo indicate that any role of CBD in pain relief does not involve direct interaction with CB 1 R and CB 2 R [22,249,250,252].…”