Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

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.

Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects

“…In support of our finding of neuron CB2R function, European labs generated principle neuron-specific Syn-Cnr2 Δ mouse strain by crossing Cnr2 f/f strain with Syn-Cre-deleter mouse strain [ 38 ]. Electrophysiological and behavioral studies of Syn-Cnr2 Δ mice found that the activation of neuronal CB2R enhanced a long-lasting membrane potential hyperpolarization by activating autonomous slow self-inhibition in neurons of hippocampus and cortex [ 38 , 39 ] and reduced neuropathic pain and anxiety [ 40 ]. By crossing the Cnr2 f/f strain with monocyte-specific LysM-Cre-deleter mice to generate LysM-Cnr2 Δ cKO mice [ 40 ], the authors found that both lymphocyte and neuron CB2Rs participate in coordinated functions in neuropathic pain.…”

“…Electrophysiological and behavioral studies of Syn-Cnr2 Δ mice found that the activation of neuronal CB2R enhanced a long-lasting membrane potential hyperpolarization by activating autonomous slow self-inhibition in neurons of hippocampus and cortex [ 38 , 39 ] and reduced neuropathic pain and anxiety [ 40 ]. By crossing the Cnr2 f/f strain with monocyte-specific LysM-Cre-deleter mice to generate LysM-Cnr2 Δ cKO mice [ 40 ], the authors found that both lymphocyte and neuron CB2Rs participate in coordinated functions in neuropathic pain. An intriguing observation is that lymphocytes participate in CB2R induced antinociception by infiltration into dorsal root ganglia (DRG) of the injured nerve and transferred their high gradient CB2R to low gradient neuron CB2R [ 40 ].…”

“…However, CB2R cell-type-specific functional studies lagged behind those of CB1R and are only reported in recent years [ 2 , 38 , 39 , 40 ]. CB2R is known to be enriched in blood leukocytes such as different B and T cells, monocytes, macrophages, natural killer cells, neutrophils, eosinophils, basophils, mast cells, [ 41 , 42 ] and plays important roles in immunomodulatory and anti-inflammation resolution by regulating cytokine release, apoptosis, autophagy, induction of T helper cells, suppression of macrophage infiltration, and lymphocyte proliferation [ 43 , 44 ].…”

CB2 Receptor in Microglia: The Guardian of Self-Control

“…On the contrary, another study suggested that rather neuronal and lymphoid and not myeloid CB2R is important for nociception after PNL [98]. This was shown by an increase in self-administration of a selective CB2R agonist, and an increased nociception after deletion of CB2R from neurons, but not from myeloid cells.…”

“…As far as we know two groups independently generated Cnr2 fl/fl animals [21,124]. Up to date Cnr2 fl/fl were further crossed with three different cre-expressing mouse lines: Syn1-cre (B6.Cg-Tg(Syn1-cre)671Jxm/J) for neuron-specific deletion [21,97,98], DAT-cre for a specific deletion in midbrain dopaminergic neurons [124] and LysM-cre (B6.129P2-Lyz2 tm1(cre)Ifo/J) animals for CB2 deletion in myeloid cells [97,98].…”