The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

Abstract

Pain is the most common manifestation of both acute and chronic inflammation that often challenges patients with rheumatic disease. Simply, we attribute this to local joint changes of pH in joints, the formation of radicals, enhanced joint pressure, or cytokine release acting on local nerves to produce pain. However, there is a more complex interplay of interactions between cytokines, mediators of inflammation, and ion channels that influence the final immune response and our perception of pain. Endocannabinoids, a group of less well-known endogenous bioactive lipids, have such manifold immunomodulatory effects able to influence both inflammation and pain. In this review, we overview the endocannabinoid system, its role in pain, inflammation, and immune regulation, and highlight the emerging challenges and therapeutic hopes.

Keywords: Endocannabinoids; arthritis; inflammation; pain.

Figure 1

Main pathways for the biosynthesis and degradation of the two main endocannabinoids: anandamide and 2-AG (17)

Figure 2

The inactivation of endocannabinoids FAAH: fatty acid amide hydrolase; MAGL: monoacylglycerol lipase; AMT: anandamide membrane transport (19)

Figure 3

Overview of the endocannabinoid-mediated synaptic signaling. (1) Action potential generated and cytoplasmic vesicles fuse with presynaptic membrane to release neurotransmitters (NT). (2) Binding of neurotransmitter on postsynaptic membrane receptors causes Ca2+ accumulation, depolarization of the membrane, and activation of calcium-dependent enzymes responsible for the biosynthesis of endocannabinoids (PL, DAGL). (3) Endocannabinoid retrograde transport and CB receptor activation. (4) Target signaling pathways reduce neurotransmitter release: (4a) suppression of adenyl cyclase (AC) activity, (4b) activation of protein kinase cascades, (4c) modulation of Ca2+ and K+ ion channels and membrane hyperpolarization and inhibition of NT release. NT: neurotransmitter; iGluR: ionotropic glutamate receptor; mGluR: metabotropic glutamate receptor; PIP2: phosphatidylinositol bisphosphate; DAG: diacylglicerol; 2-AG: 2-arachidonoylglycerol; NAPE: N-arachidonoyl-phosphatidylethanolamine; AEA: anandamide; PLC: phospholipase C; DAGL: diacylglycerol lipase; PLD: phospholipase D; AC: adenyl cyclase; cAMP: cyclic AMP; MAPK: mitogen-activated protein kinase; PKC: protein kinase C; X+: unspecific cation32

Figure 4

Neural reflex immunity circuits. Various stimuli such as (a) inflammatory (e.g., IL1), (b) bacterial, (c) acupuncture, or (d) pressure/acupuncture are detected by sensory afferent nerves and relayed to interneurons located in the spinal cord/brainstem. The generated efferent signals work to dampen the innate immune responses signaling through (a) efferent neurons of the hypothalamic-pituitary adrenal (HPA) axis, (c) via the release of dopamine via the adrenal medulla, or (b) via the local axon-axon reflex which suppress the innate immune responses by cytokine release and immune cell activation. Efferent signals sent via the sympathetic system (d) or vagus nerve (e), release neurotransmitters that influence the immune response (75)