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Review
, 367 (1607), 3300-11

Dynamic Changes to the Endocannabinoid System in Models of Chronic Pain

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Review

Dynamic Changes to the Endocannabinoid System in Models of Chronic Pain

Devi Rani Sagar et al. Philos Trans R Soc Lond B Biol Sci.

Abstract

The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

Figures

Figure 1.
Figure 1.
(a) Under basal conditions, endocannabinoids modulate spinal nociceptive transmission through activation of pre- [10,24] and post-synaptic [25] CB1 receptors expressed on primary afferent fibres. Increased intracellular calcium ([↑Ca2+]i) in postsynaptic neurons can stimulate AEA and 2-AG production and consequently activation of CB1 receptors. AEA and 2-AG are broken down via their respective catabolic enzymes (AEA: FAAH, 2-AG: MAGL) in the pre- and post-synaptic neurons and potentially also by resting microglia, which may express cannabinoid CB2 receptors. (b) In chronic pain states, activated spinal microglia and astrocytes release sensitizing factors, which can further facilitate the already-enhanced nociceptive signalling in the spinal cord. Under these conditions, endocannabinoid production is augmented in the spinal cord [26,27], and enzymes such as cytochrome p450 (CYP) and upregulation of cycloxygenase-2 (COX-2) and lipoxygenases (15-LOX) may provide alternative catabolic pathways for these endocannabinoids. These alternative pathways can result in the production of biologically active metabolites that modulate nociceptive transmission [–30]. The generation of prostaglandin glycerol esters such as PGE2-G and prostaglandin ethanolamides (prostamide) such as prostamide F (PMF) can facilitate neuronal responses, although the mechanisms for these effects are currently unclear. One possibility is activation of prostaglandin FP receptors, producing increased intracellular calcium, leading to enhanced neuronal responses. Cannabinoid receptor expression is upregulated in the spinal cord; however, the exact location is not yet clear. CB1 receptors are also present on astrocytes [31], while CB2 receptors are present on microglia [32] and are thought to be upregulated on pre-synaptic terminals [33] following nerve injury. Spinal administration of CB2 receptor agonists inhibits responses of WDR neurons and thus an increase in postsynaptic expression of CB2 receptors cannot be ruled out. CB2 receptors appear to play a modulatory role in chronic pain state, with exacerbated nociceptive responses present in CB2 null mice [34]. +denotes activation;−denotes inhibition; dashed line denotes enzymatic breakdown.

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