Current state of transient receptor potential (TRP) channel drug discovery, illustrated by phase of development. Chemical structures of lead molecules have been inserted where known (see REFS 133,134). Patent examples are drawn where the structure is not published (from REFS 135,136).

Noxious and thermal stimuli act directly on the peripheral terminals of nociceptors to activate these sensory fibres. Many of the transduction channels that convert thermal, mechanical or chemical stimuli into electrical activity are transient receptor potential (TRP) channels. Activation of the peripheral terminal leads to action potential signalling towards the central nervous system (CNS) and a local release of vasoactive peptides that produce neurogenic inflammation. Although TRPV1 and TRPA1 are co-expressed in nociceptors TRPM8 is largely expressed in a unique set of sensory neurons without co-expression of TRV1 and TRPA1 (represented by bracket around TRPM8). Some TRP channels are expressed on keratinocytes and these cells may respond to noxious thermal stimuli by releasing a signal molecule, possibly ATP that then acts on the nociceptor. The nociceptor presynaptic terminal contains excitatory amino acid and peptide transmitters, the release of which is modulated by several TRP channels. The dashed arrows in the figure represent unknown signalling molecules, possibly endovanilloid lipids. CGRP, calcitonin gene-related peptide.

Pain can be divided into three broad categories: nociceptive, inflammatory and neuropathic. This division is based on the initiating stimulus (presence of a noxious stimulus, inflammation or neural damage); the neural substrate involved (nociceptors or non-nociceptors and the relative contribution/involvement of the peripheral nervous system (PNS) or central nervous system (CNS)); and the relative involvement of transient receptor potential (TRP) channels; the typical clinical conditions; the biological role of pain; and the pain threshold. Nociceptive pain is generated by noxious stimuli that act on nociceptors in the PNS, and which, for thermal stimuli and chemical irritants, depend on TRP channels. This pain occurs clinically in the setting of acute trauma, is protective and serves to warn of damage. Inflammatory pain occurs in the presence of damaged or inflamed tissue. Inflammatory mediators can sensitize nociceptors, which involves alterations in TRP channel threshold. Central changes are also induced (central sensitization) such that pain can be recruited by activation of non-nociceptors. This clinical pain state is typically reversible and associated with hypersensitivity (noxious stimuli are no longer needed to evoke pain). Neuropathic pain results from damage and lesions to the nervous system. The pathophysiological changes responsible for the spontaneous pain and pain hypersensitivity experienced by patients occur both in the PNS and CNS and represent non-adaptive pathological changes. Some TRP channel antagonists reduce such pain but their involvement is not well understood.

Peripheral inflammation produces multiple inflammatory mediators (sensitizers) that act on their cognate receptors expressed by nociceptors to activate intracellular signal transduction pathways. These pathways can phosphorylate transient receptor potential (TRP) channels and thereby alter their trafficking to the membrane and their thresholds and kinetics. Several growth factors produced during inflammation, most notably nerve growth factor (NGF), are retrogradely transported to the cell body of the nociceptors in the dorsal root ganglion. At the dorsal root ganglion, these growth factors — through intracellular signalling pathways, such as p38 MAP kinase — increase the expression of TRP channels, which are then transported to the peripheral terminal. Changes in transcription and translation of TRP channels and other proteins can switch the chemical phenotype of the neurons from their state in naive conditions to an altered state during inflammation. The net effect of these changes is peripheral sensitization; that is, a reduction in the pain threshold at the site of inflamed tissue. B₂, bradykinin receptor B2; ERK, extracellular signal-regulated kinase; ETAR, endothelin receptor type A; GDNF, glial-cell-derived neurotrophic factor; NK1, neurokinin receptor 1; PAR₂, protease-activated receptor 2; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PK, protein kinase; PKR, prokineticin receptor; TNFα, tumour necrosis factor α; TNFR1, TNF receptor 1; TRKA, tyrosine kinase receptor A.

Transient receptor potential (TRP) channel antagonists as analgesics (a). Inhibition of TRP channels may produce analgesia by preventing transduction in the periphery, acting on channels expressed in keratinocytes or nociceptors, reducing ectopic activity generated by TRP channels along the axon and by reducing transmitter release as well as possibly acting on central neurons. The small hexagons represent TRPV1 channels at different anatomical locations, the vertical line share the different sites of actions of TRPV1 antagonists and the horizontal line shows the flow of nociceptive information from the periphery to the central nervous system. TRP channel agonists as analgesics (b–d). Activation of TRP channels may reduce pain by desensitizing the TRP channel to reduce pain transduction (this effect is transient and fully reversible; b); by producing sufficient calcium influx to ablate the axon at the site of application (represented by dotted lines on the left; c), producing long-lasting but potentially reversible morphological change, or ablating the whole neuron as a result of death of the cell body (represented by dotted circle), which is irreversible (c); and by driving inhibitory circuits, as for activation of cool-sensing TRPM8 expressing neurons, which represent the channels on the peripheral terminal (d). For approaches b and c the agonist will cause pain until desensitization is achieved or neuronal ablation occurs and may require a general anaesthetic. Evidence for efficacy for topical capsaicin in rheumatic conditions is lacking161, and that for resiniferatoxin for lower urinary tract symptoms is inconclusive162. However, there seems to be efficacy for topical low-dose capsaicin for post-herpetic neuralgia163 and high-dose capsaicin for pain experienced in HIV127.