Abstract
Evidence shows bidirectional crosstalk between neurons and glia, suggesting that glia play an active role in synaptic plasticity leading to chronic pain. Importantly, gliosis has been implicated in the development and maintenance of hyperalgesia or allodynia following chronic inflammation or nerve injury. Anandamide (AEA) and 2- arachidonoylglycerol (2-AG), or the lipoamino acid N-arachydonoyldopamine (NADA), are fatty acid derivative neuro- transmitters, named endocannabinoids (eCBs). These perform several biological actions, via the activation of cannabinoid type 1 and 2 (CB1/CB2) receptors belonging to the G-protein-coupled receptor family. The eCBs are produced on de- mand by neurons or glial cells and it has been suggested that they might be involved in the crosstalk between astrocytes, microglia, oligodendrocytes and neurons. In chronic pain, the modified glial or neural activity also seems to be associated with changes in eCB levels in pain processing areas either in the spinal cord or the brain. The activation of the eCB sys- tem in microglia or astrocytes could be crucial in modulating axonal growth and synaptogenesis at the base of neural phe- notypic changes. Furthermore, changes in eCBs levels have been suggested to affect the destiny of cells: death or survival may depend on a specific pain condition. Thus, although eCBs are emerging as neurotransmitters responsible for the regu- lation of glia-neuron crosstalk in chronic pain, the precise mechanisms leading to eCB production, the origin and the time- course of eCB release, the eCB release switch from one cell type to the other and their movement or catabolism across the glial or neural cell membrane nevertheless still remain unknown. These issues together with alternative eCB targets will be addressed in the current review.
Highlights
Neuropathic pain is a debilitating condition which has a serious impact on the quality of life
FKN is constitutively expressed by spinal cord and sensory neurons in the dorsal root ganglia (DRGs) [84,85,86], while CX3CR1 is exclusively expressed by microglial cells [85] and, after peripheral nerve injury it is widely up-regulated in microglia [85]
In one of our recent studies [28], we demonstrated that CB2 receptor stimulation induced an analgesic effect associated with a reduction in the pro-inflammatory (IFN- and IL-1) and an enhancement of anti-inflammatory (IL-10) mediators within the spinal cord
Summary
Neuropathic pain is a debilitating condition which has a serious impact on the quality of life. Glial cells involved in mediating inflammatory processes are resident within the spinal cord and include both astroglia and microglia, the latter of which has been directly implicated in the initiation of peripheral injury-induced pain [12]. An increased expression of CB2 receptors has been shown in microglial cells, as well as in astrocytes, in neuropathic pain conditions [25, 26].
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