Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation

Abstract

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

The Effect of Exercise Training and Royal Jelly on Hippocampal Cannabinoid-1-Receptors and Pain Threshold in Experimental Autoimmune Encephalomyelitis in Rats as Animal Model of Multiple Sclerosis

“…So, its related mechanisms must be investigated from different perspectives, including hyperactivity of pain sensors in the peripheral organs to physiological and pathological damage to peripheral nerves [ 32 ]. In addition to impaired neurotrophins, endorphins [ 32 ] and cannabinoids are other mechanisms involved in peripheral pain, of which impaired glutamate and glutamate receptors, impaired expression of inotropic, increased activity and expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA), and tumor necrosis factor α (TNFα) and IL-1β can be noted [ 33 ].…”

Role of Epigenetic Mechanisms in Chronic Pain

“…As cannabinoid or opioid administration often loses efficacy over time in chronic pain patients, this finding represents a potential explanation for their pharmacological pattern. Both CB receptors have additionally been associated to modulation of inflammatory pain and, more generally, inflammation in diverse cell types [ 84 , 85 , 86 , 87 ]; it would therefore be interesting to assess the epigenetic regulation of expression of CB receptors under inflammatory pain conditions.…”

Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis

“…19 It is perhaps best known for playing important roles in food intake and energy metabolism, regulation of the hypothalamic-pituitary-adrenal axis, pain transmission, and a variety of emotional and behavioral conditions. 14,[19][20][21][22][23][24][25] The ECS was discovered after the isolation of D 9 tetrahydrocannabinol (THC) as the major psychoactive constituent of cannabis. 26 This finding led to the development of ligands that were used to identify the receptors for cannabis.…”