Applications of Cannabinoids in Neuropathic Pain: An Updated Review

Abstract

Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.

FIG. 1:

Chemical structures of some phytocannabinoids and synthetic cannabinoids

FIG. 2:

Localization of the cannabinoid receptors in the pain perception system of humans. The cannabinoid receptor 1 (CB1) is highly expressed in the peripheral nervous system (PNS) such as the sympathetic nerve terminal and in the brain (CNS). They are also observed in the dorsal root ganglion, dermic nerve endings of the primary sensory neurons. Cannabinoid receptor 2 (CB2) is less abundant in the CNS and PNS as compared to CB1.

FIG. 3:

Therapeutic applications of cannabinoids

FIG. 4:

Types of pain. Neuropathic pain is sub-type of chronic pain and could be central/peripheral. Peripheral neuropathic pain includes diabetic neuropathy, CIPN and HIV related neuropathic pain.

FIG. 5:

Plausible mechanism of action of cannabinoids in protecting peripheral neurons against various disease conditions. Cannabinoids have been found to activate TRPV1 ion channels, GPR55 and 5HT1A receptors including CB1 and CB2 receptors. By activation of these receptors or by regulating the downstream AMPK, Nrf2, NF-κB and BDNF cell signalling pathways, Cannabinoids improved neurogenesis, increased autophagosomes formation, increased mitochondrial biogenesis and improved mitochondrial function and enhanced antioxidant response with decreasing inflammation in different conditions of neuropathy. AMPK, adenosine monophosphate-activated protein kinase; Atg, anti-thymocyte globulin; BDNF, brain-derived neurotrophic factor; FIP200, FAK family kinase-interacting protein of 200 kDa; GSH, Glutathione; HO1, heme oxygenase 1; mTOR, mechanistic target of rapamycin; SIRT1, silent mating type information regulation 2 homolog 1; NRF, nuclear respiratory factor; Nrf2, nuclear factor erythroid 2 (NFE2)-related factor 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PGC-lα, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TFAM, mitochondrial transcription factor; Ulk1, unc-51 like autophagy activating kinase; VPS34, vacuolar protein sorting 34.