Fig. 1
From: Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain
Peripheral sensitization. Activation of peripheral nociceptors on the skin in response to stimuli, such as heat, injury or mechanical pressure, initiates the release of chemical mediators at the site of injury (peripheral sensitization). Peripheral terminals respond to noxious stimuli through ion channels such as TRP, ASIC, HCN, and P2X receptors, as well as TrkA, TLR, TNFR, IL-1R and GPCRs such as bradykinin (BK), neurokinin (NK) which indirectly modulate ion channels and intracellular signaling pathways. When a threshold depolarization is reached, voltage-gated sodium channels (Nav1.7/1.8) are activated, which generate an action potential. At this point voltage-gated potassium channels (Kv4.2) open and repolarize the membrane, while NaV channels close and the neuron returns to a resting state. The action potential then propagates along the axon to the spinal neuron. TRP transient receptor potential, ASIC acid sensing ion channels; HCN hyperpolarization-activated cyclic nucleotide-gated channel, P2X3R purinergic receptor 3, TrkA tropomyosin receptor kinase A, CCL2/ CXCL1 chemokines, PGE2 prostaglandin 2, TNF tumor necrosis factor, IL-1R interleukin 1 receptor, TLR toll-like receptor, GPCR G protein-coupled receptor