Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity

Abstract

BackgroundThe function of the Cannabinoid 1 receptor (CB1R) in the development of neuropathic pain is not clear. Mounting evidence suggest that CB1R expression and activation may contribute to pain. Cannabinoid 1 receptor knockout mice (CB1R−/−) generated on a C57Bl/6 background exhibit hypoalgesia in the hotplate assay and formalin test. These findings suggest that Cannabinoid 1 receptor expression mediates the responses to at least some types of painful stimuli. By using this mouse line, we sought to determine if the lack of Cannabinoid 1 receptor unveils a general hypoalgesic phenotype, including protection against the development of neuropathic pain. The acetone test was used to measure cold sensitivity, the electronic von Frey was used to measure mechanical thresholds before and after spared-nerve injury, and analysis of footprint patterns was conducted to determine if motor function is differentially affected after nerve-injury in mice with varying levels of Cannabinoid 1 receptor.ResultsAt baseline, CB1R−/− mice were hypersensitive in the acetone test, and this phenotype was maintained after spared-nerve injury. Using calcium imaging of lumbar dorsal root ganglion (DRG) cultures, a higher percentage of neurons isolated from CB1R−/− mice were menthol sensitive relative to DRG isolated from wild-type (CB1R+/+) mice. Baseline mechanical thresholds did not differ among genotypes, and mechanical hypersensitivity developed similarly in the first two weeks following spared-nerve injury (SNI). At two weeks post-SNI, CB1R−/− mice recovered significantly from mechanical hypersensitivity, while the CB1R+/+ mice did not. Heterozygous knockouts (CB1R+/−) transiently developed cold allodynia only after injury, but recovered mechanical thresholds to a similar extent as the CB1R−/− mice. Sciatic functional indices, which reflect overall nerve health, and alternation coefficients, which indicate uniformity of strides, were not significantly different among genotypes.ConclusionCold allodynia and significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R−/− mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice.

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

“…The role of TRPM8 in the development of cold hypersensitivity has been demonstrated previously in animal and human CIPN studies (Gauchan et al, 2009; Kono et al, 2012; Ta et al, 2010). A recent study showed that global CB1R deletion exaggerated the responses to hindpaw cold stimulation in naive and neuropathic mice suggesting that CB1R activation may protect against the development of cold allodynia (Sideris et al, 2016). In contrast, other studies have demonstrated a lack of such effects of CB1R deletion on cold sensitivity before and after induction of neuropathy (Castane et al, 2006; Deng et al, 2015).…”

The Neuroimmunology of Chronic Pain: From Rodents to Humans

“…Among these, CB1R has been identified as a viable candidate in controlling pain and inflammation (Kunos et al, 2009;Milligan et al, 2020). Global CB1R KO studies have demonstrated the necessity of CB1R action for both endogenous and therapeutically induced pain inhibition (Sideris et al, 2016;Bajic et al, 2018). Although these studies have established the analgesic function of CB1R, they have failed to distinguish the most critical loci for analgesic action.…”

The Basic Science of Cannabinoids

“…The earliest studies describing the importance of the eCB system in the modulation of pain behaviors came from global deletion of the CB1 receptor, 94 which revealed receptor modulation of thermal and tactile sensitivity, and reinforcing properties of opioids. 94–97 Pharmacological studies using brain-impenetrant or site-specific injections of drugs and conditional knock out mouse studies have revealed that peripheral, spinal, and supraspinal sites are involved in cannabinoid-mediated analgesia. 98–103…”