Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity.

Zachary K Ford,Steve Davidson,Sisi Chen,Alexander Bunk,Feni Kadakia,Ashlie N Reker

doi:10.3389/fpain.2021.721332

Zachary K Ford, Steve Davidson + Show 4 more

Open Access

https://doi.org/10.3389/fpain.2021.721332

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Abstract

Cannabinoid receptors have been identified as potential targets for analgesia from studies on animal physiology and behavior, and from human clinical trials. Here, we sought to improve translational understanding of the mechanisms of cannabinoid-mediated peripheral analgesia. Human lumbar dorsal root ganglia were rapidly recovered from organ donors to perform physiological and anatomical investigations into the potential for cannabinoids to mediate analgesia at the level of the peripheral nervous system. Anatomical characterization of in situ gene expression and immunoreactivity showed that 61 and 53% of human sensory neurons express the CB1 gene and receptor, respectively. Calcium influx evoked by the algogen capsaicin was measured by Fura-2AM in dissociated human sensory neurons pre-exposed to the inflammatory mediator prostaglandin E2 (PGE2) alone or together with CB13 (1 μM), a cannabinoid agonist with limited blood–brain barrier permeability. Both a higher proportion of neurons and a greater magnitude of response to capsaicin were observed after exposure to CB13, indicating cannabinoid-mediated sensitization. In contrast, membrane properties measured by patch-clamp electrophysiology demonstrated that CB13 suppressed excitability and reduced action potential discharge in PGE2-pre-incubated sensory neurons, suggesting the suppression of sensitization. This bidirectional modulation of sensory neuron activity suggests that cannabinoids may suppress overall membrane excitability while simultaneously enhancing responsivity to TRPV1-mediated stimuli. We conclude that peripherally restricted cannabinoids may have both pro- and anti-nociceptive effects in human sensory neurons.

Highlights

Some clinical studies have noted analgesic benefits of cannabinoids for various chronic pain syndromes, including neuropathic, rheumatoid arthritis, and cancer pain [1,2,3,4]
Cannabinoid receptors are found in rodent peripheral nervous system, in the dorsal root ganglia, and the CB1 receptor subtype is localized to rodent sensory neurons, including nociceptors [10,11,12,13,14]
We examined the expression of cannabinoid receptor type 1 protein and gene in human dorsal root ganglia and found it to be expressed abundantly in many sensory neurons, both large and small

Summary

Introduction

Some clinical studies have noted analgesic benefits of cannabinoids for various chronic pain syndromes, including neuropathic, rheumatoid arthritis, and cancer pain [1,2,3,4]. Cannabinoid receptors are highly expressed within most parts of the nervous system, including within cognitive, affective, and motivational systems, and cannabinoid ligands can lead to unwanted side effects such as psychoactivity, dependence, and sedation [8]. These secondary effects can make measurement and determination of the specific anti-nociceptive effects of systemic cannabinoids difficult to assess. Animal studies have shown that the activation of CB receptors modulates peripheral neural excitability and sensitization consistent with an anti-nociceptive phenotype. Cannabinoids, likewise, suppress action potentials in nociceptive c-fibers [17]

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