Abstract
Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2; however, the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.
Highlights
Cannabinoid CB2 receptor (CB2) agonists show efficacy in animal models of chronic inflammatory and neuropathic pain, suggesting that they may be effective inhibitors of persistent pain in humans (Bie et al, 2018; Maldonado et al, 2016; Shang and Tang, 2017)
Antinociception is a desirable characteristic for drugs targeting chronic neuropathic pain, it is unclear whether the pain-relieving effects of the CB2 agonist would be sufficient to elicit drug-taking behavior in mice and the cell populations involved
This work shows a protective function of CB2 from neurons and lymphocytes on spontaneous neuropathic pain and the involvement of these cell populations in CB2-induced antinociception, as revealed by increased self-administration of the CB2 agonist JWH133 in mice defective in lymphocyte and neuronal CB2
Summary
Cannabinoid CB2 receptor (CB2) agonists show efficacy in animal models of chronic inflammatory and neuropathic pain, suggesting that they may be effective inhibitors of persistent pain in humans (Bie et al, 2018; Maldonado et al, 2016; Shang and Tang, 2017). Operant paradigms in which animals voluntarily self-administer analgesic compounds can provide high translatability and identify in the same experimental approach potential addictive properties of the drugs (Mogil, 2009; Mogil et al, 2010; O’Connor et al, 2011). In this line, a previous work using a CB2 agonist, AM1241, showed drug-taking behavior in nerve-injured rats and not in sham-operated animals, suggesting spontaneous pain relief and lack of abuse potential of CB2agonists (Gutierrez et al, 2011), the possible cell populations and mechanisms involved remain unknown. Immunological blockade of lymphocyte extravasation was used to investigate the effect of this cell type on spontaneous neuropathic pain and its involvement on the pain-relieving effects of the cannabinoid CB2 agonist
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