Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain

Abstract

Background Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain. Methods A partial sciatic nerve ligation was performed to wild‐type (WT) and Fmr1KO mice having (HzCB2 and Fmr1KO‐HzCB2, respectively) or not (WT and Fmr1KO mice) a partial deletion of CB2 to investigate the participation of the endocannabinoid system on the pain‐resistant phenotype of Fmr1KO mice. Results Nerve injury induced canonical hypersensitivity in WT and HzCB2 mice, whereas this increased pain sensitivity was absent in Fmr1KO mice. Interestingly, Fmr1KO mice partially lacking CB2 lost this protection against neuropathic pain. Similarly, pain‐induced depressive‐like behaviour was observed in WT, HzCB2 and Fmr1KO‐HzCB2 mice, but not in Fmr1KO littermates. Nerve injury evoked different alterations in WT and Fmr1KO mice at spinal and supra‐spinal levels that correlated with these nociceptive and emotional alterations. Conclusions This work shows that CB2 is necessary for the protection against neuropathic pain observed in Fmr1KO mice, raising the interest in targeting this receptor for the treatment of neuropathic pain. Significance Neuropathic pain is a complex chronic pain condition and current treatments are limited by the lack of efficacy and the incidence of important side effects. Our findings show that the pain‐resistant phenotype of Fmr1KO mice against nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of the cannabinoid receptor CB2, raising the interest in targeting this receptor for neuropathic pain treatment. Additional multidisciplinary studies more closely related to human pain experience should be conducted to explore the potential use of cannabinoids as adequate analgesic tools.

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome

“…CBD is a compound typically derived from hemp that targets CB1, CB2 receptors and is an allosteric modulator of μ- and δ-opioid receptors. Evidence in FMR1 knockout mice suggests CB2 receptor is necessary for protection against neuropathic pain, raising interest in targeting this receptor for treatment ( 77 ). A controlled trial examined pain in patients with multiple sclerosis, spinal cord, and other neurological conditions found pain control improved with CBD ( 78 ) in addition to two other studies that found pain relief ( 79 , 80 ).…”

Hyperexcitability of Sensory Neurons in Fragile X Mouse Model

“…A previous study showed that loss of FMRP decreases nociceptive sensitization in adult mice, even though the basal nociceptive thresholds were intact ( Price et al, 2007 ). Recent evidence also indicates impaired pain induction and perception in the FXS mouse model, including reduced neuropathic pain ( Ramirez-Lopez et al, 2021 ), and visceral pain ( Yang et al, 2020 ). Future in vivo studies will be needed to determine whether and how increased excitability of nociceptive neurons in adolescent mice we observed here is linked to abnormal pain induction or perception in FXS mice.…”

“…Individuals with FXS commonly exhibit somatosensory deficits, such as hypersensitivity to touch ( Cascio, 2010 ), Self-injurious behaviors in Fragile X individuals ( Arron et al, 2011 ; Crawford et al, 2019 ) are also indicative of abnormal pain perception. Impaired pain induction and perception are also observed in the FXS mouse model, including reduced induction of neuropathic pain ( Ramirez-Lopez et al, 2021 ), and insensitivity to visceral pain ( Yang et al, 2020 ). These and other sensory deficits have been largely attributed to alterations in cortical sensory processing with a wide range of excitability deficits identified in somatosensory cortex of FXS models at neuronal, circuit, and network levels ( Contractor et al, 2015 ).…”

Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice

“…An increasing number of studies explore the use of exogenous cannabinoids, namely, tetrahydrocannabinol (THC) and cannabidiol (CBD), in various disorders [62,[75][76][77][78][79][80][81], including FXS and ASD [36,58,[82][83][84][85]. Cannabis and targeted eCB system modulation ameliorate symptoms associated with FXS and ASD, including cognitive deficits [37,38], anxiety and hyperactivity [36,39,82], sociability [59,74], restlessness [36], nociception [40,86], and audiogenic seizure susceptibility [39]. However, there is limited knowledge on the neurophysiological effects induced by cannabinoids and the specific mechanisms of how cannabinoids ameliorate FXS symptomatology.…”