There is currently substantial evidence indicating multiple key roles of several TRP channels not only in detecting noxious stimuli and signalling within the pain system, but also in pain arising without a well-defined noxious input, e.g. when it outlasts the initial tissue damage and/or inflammation and becomes chronic. TRP channels are ubiquitous in sensory neurones, where they respond to mechanical, thermal and chemical stimuli and also interact with GPCR and cytokine receptors [90]. When their stimulation becomes excessive or, alternatively, their sensitivity to the stimuli becomes abnormally enhanced, activation of these channels causes painful sensations. The most obvious examples of such responses are those caused by compounds known to elicit unpleasant or painful sensations, such as cinnamaldehyde, mustard oil, gingerol, capsaicin and icilin-molecules now known as agonists of specific excitatory TRP subtypes, as well as thermal pain due to excessive cold or hot temperature mediated by thermosensitive TRPs.

The founding TRP member triggering much interest in the TRP-pain connection was identified by Julius and co-workers in 1997 as a polymodal sensor TRPV1, which is both the capsaicin receptor and heat-activated Ca²⁺-permeable channel [91]. This discovery was followed by the identification of the menthol and cold receptor TRPM8 in 2002 [92] and, somewhat later, noxious cold and pungent compounds (such as mustard oil) sensitive TRPA1 [93-95], which substantiated a more general role for TRP channels both in thermosensation and pain. Other TRPs widely discussed in connection with pain include TRPV2, TRPV3 and TRPV4 [5-8, 96, 97]. It is interesting to note that all these “painful” TRP channels physiologically are primarily thermosensitive channels (albeit they differ in the temperature range needed for their activation, from <17 ^OC for TRPA1 to >50 ^OC for TRPV2). However, it may be argued that thermal sensitivity is not necessarily the sole reason for their role in nociception [5]. In experimental models of pain, siRNA interference, antisense approach and knockout studies firmly confirmed the important roles of TRPV1, TRPV4 and TRPA1 channels in nociceptive signalling in vivo (reviewed in [5]).

TRPV2 knockout mice became available more recently, and they showed surprisingly normal heat responsiveness, thermal and mechanical nociception, including under inflammatory or neuropathic conditions [98]. With regard to TRPM8 the results are mixed – one study demonstrated no role of TRPM8 (unlike TRPA1) in cold hyperalgesia after spinal nerve injury [99], yet in chronic neuropathic pain TRPM8 activation produced analgesia [100]. Recently with the use of ablation of TRPV1 or TRPM8 expressing cells, significantly decreased responses to noxious heat and cold, respectively, have been demonstrated in mice [101].

There is also substantial evidence demonstrating that TRPV1 and TRPV4 channels are involved in inflammatory hyperalgesia, while more recently TRPC1 and TRPC6 have been implicated in mechanical hyperalgesia (reviewed in [6]). In addition, expressed in macrophages and microglia TRPM2, which is primarily a sensor for reactive oxygen species, contributes to the pathogenesis of inflammatory and neuropathic pain [102]. TRPM3, the most recently identified thermosensitive TRP, can detect noxious heat and is involved in the development of inflammatory heat hyperalgesia [103].

One subject that attracted particularly large body of research is TRP sensitization produced by inflammation mediators, such as ATP, the cytokines, prostaglandins, bradykinin and neuropeptides (e.g. substance P). The role of TRPV1 in inflammatory pain has been most extensively investigated. Mediators of inflammation and the second messengers they engage strongly sensitize TRPV1 thus causing thermal hyperalgesia. Signal transduction involves both protein kinase A (PKA) and protein kinase C (PKC) mediated phosphorylation of TRPV1 leading to increased channel translocation to the plasma membrane and enhanced channel activity, respectively (reviewed in [6]). Inhibition of the AKAP79/150 protein prevents TRPV1 sensitization, at least that caused by bradykinin and PGE2 and mediated by PKA [104].

The above discussed channels, TRPV1 and TRPA1 in particular, are thus believed to be very promising molecular targets for the next generation of analgesics, although the real success of such drugs is yet to be seen [7, 8]. Since multiple TRP subtypes are involved in pain transduction, the possibility of developing nonselective TRP antagonist as a useful strategy for pain treatment has been raised [8]. However, there is also valid concern that, giving the channels are widely expressed in the nervous system and on the periphery and that they can structurally and functionally interact with other TRP subtypes, such drugs (either subtype selective or nonselective) may have a number of side effects. One spectacular example of such problems is represented by the attempts to develop TRPV1 antagonists, which did not progress beyond testing in Phase II trials due to problems with the regulation of body temperature and detection of noxious heat [97]. Therefore, strategies aimed at preventing channel translocation to the plasma membrane or enhancement of channel sensitivity, rather than channel blockade, are also advocated [7]. As will be discussed in the following section, in some cases abrogation of channel sensitization can indeed be achieved through the action of cannabinoids.