Nociceptor sensitization in pain pathogenesis

Abstract

The incidence of chronic pain is estimated to be 20-25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain.

Figure 1

Heterogeneity of nociceptors. (a–c) Nociceptors can be subclassified by an array of anatomical, physiological and biochemical criteria. One common criterion is the response profile of the afferent: afferents that respond to mechanical, thermal and chemical stimuli are referred to as polymodal nociceptors (a), those that respond to mechanical and cold stimuli are referred to as C-MC (mechano-cold) fibers (b), and those that do not respond to mechanical stimuli are referred to as MIAs (c). Even within these classifications there is tremendous heterogeneity, with differences in the particular molecules that underlie transduction, action potential initiation and propagation, as well as in the channels and receptors that can modulate each of these processes. There are also differences in the transmitters that are released, with more recent data pointing to differences in the proteins that are responsible for vesicle filling. With increasing evidence that MIAs are particularly important in various pain states, the identification of unique patterns of chemosensitivity and the mechanisms that underlie the emergence of mechanosensitivity in these afferents might yield new approaches for the treatment of pain. RTK, receptor tyrosine kinase; SK, small-conductance Ca²⁺-dependent potassium channel; VGCC, voltage-gated calcium channel.

Figure 2

Activation and sensitization of nociceptors. (a) Transduction can involve both direct and indirect pathways. The ion channel TRPV1, for example, can be directly opened by increases in temperature or by chemicals released from resident (mast) and recruited (polymorphonuclear leukocyte; PMNL) immune cells, epithelial cells, Schwann cells, fibroblasts and sympathetic post-ganglionic neurons (SPGN). (b) There are multiple points of interaction between second messenger pathways that are engaged after nociceptor activation, including at the levels of signaling molecules such as Ca²⁺, effector molecules such as PKCε, and common targets, such as TRPV1 and NaV1.8 (not shown) for the pathways activated. For clarity, we have omitted positive modulation of TRPV1 by ceramide, p38, PI3K, PKCε and PKA. Also not shown is the translocation of TRPV1 to the cell surface, which may contribute to injury-induced increases in channel activity. (c) Sensitization of nociceptors also involves positive feedback. Activation of ion channels such as TRPV1 results in membrane depolarization and Ca²⁺ influx through TRPV1 and VGCC. Ca²⁺ influx can drive the release of neuropeptides (stored in dense core vesicles; pink) and glutamate (stored in clear vesicles; yellow), both of which can drive further activation of receptors on nociceptors and release mediators from the sources described in a. PGs, prostaglandins; OLAMs, oxidized linoleic acid meabolites; NE, norepinephrine; ER/GPR30, estrogen receptor/G protein receptor-30; 5-HT, serotonin; CaM, calmodulin; PLC, phospholipase C. DAG, diacylglycerol; IP₃, inositol triphosphate; AC, adenylate cyclase; EPAC, cAMP-activated guanine exchange factor; PI3K, phosphoinositide 3-kinase; ERK1/2, extracellular signal–regulated kinases 1 and 2; TNFR, tumor necrosis factor receptor.