Pain signaling pathways

 

The sensation of pain can be separated into neuropathic,inflammatory and nociceptive pain which are stimulated by heat, acid, mechanical pressure and cold. This pathway poster summarises the complex interplay of peripheral sensitization, central sensitization and inhibition. Download pdf

Signaling Pathways in Peripheral Pain Sensitization

The activation of receptors and channels at afferent nociceptor Aδ and C fibre terminals leads to the generation of an action potential that travels up the spinal cord to the brain for conscious pain perception. ASIC, TRPA1 and TRPV1 channels open in response to a decrease in pH and H⁺ binding, leading to Ca²⁺ and Na⁺ influx.

Inflammatory mediators produced by damaged cells and immune cells activate prostaglandin EP, bradykinin B_1/2 and cytokine receptors. Serotonin and ATP activate 5-HT_2A/3 receptor and P2X3 receptors respectively. Activation of these receptors activates ERK, p38, PKA, PLC and PKC causing release of intracellular Ca²⁺. These enzymes also increase Ca²⁺ and Na⁺ influx and inhibit K⁺ influx.

Inflammatory mediators can cause peripheral sensitization where innocuous stimuli is experienced as painful. There is increased gene translation and trafficking of ion channels and receptors, with a lowered activation threshold of the TRPV1 channel due to PKC phosphorylation.

There is also central sensitization of pain mediated by glutamate receptors and disinhibition via loss of GABA and glycine inhibition.

Signaling Pathways in Pain Inhibition

Inhibition of peripheral pain is mediated by several receptors such as GABA and glycine receptors which are expressed on afferent neurons pre-synaptically or on dorsal horn neurons post-synaptically. Activation of these receptors decreases the response to noxious stimuli through an influx of Cl^-.

Activation of α₂-adrenoceptors by noradrenaline decreases cAMP and inhibits PKA, increasing glycine receptor activity.

Dorsal horn neurons can express mAChRs which are agonised by acetylcholine, inhibiting nociception.

Opioid receptors are also expressed, responding to endogenous enkephalin and β-endorphin produced by monocytes. Opioid, CB₁ and mGlu_2/3 receptors inhibit Ca²⁺ and Na⁺ channels and activate K⁺ channels.

References

Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell. 139(2):267-84. Pan HL, Wu ZZ, Zhou HY, Chen SR, Zhang HM, Li DP (2008) Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther. 117(1):141-61. Petho G, Reeh PW (2012) Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev. 92(4):1699-775. Schaible HG (2007) Peripheral and central mechanisms of pain generation. Handb Exp Pharmacol. 177:3-28. Schaible HG, Ebersberger A, Natura G (2011) Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 13(2):210. Scholz J, Woolf CJ. (2002) Can we conquer pain? Nat Neurosci. 5 Suppl:1062-7. Woolf CJ, Ma Q (2007) Nociceptors--noxious stimulus detectors. Neuron. 5:353-64.

Pain research tools

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G protein coupled receptors Ach muscarinic Adenosine Adrenoceptors Cannabinoid Dopamine GABAB Histamine Metabotropic glutamate Neuropeptide Opioid Prostanoid Serotonin (5-HT)

Ionotropic receptors GABAA AMPA Kainate NMDA Ion channels Ca2+ channels K+ channels Sodium channels TRP channels

Enzymes ATPase / GTPase Caspase Kinase Transferase Phosphatase Protein-tyrosine phosphatase Cell signaling Hedgehog signaling Wnt signaling