PerspectiveSensory Perception

Intracellular Signaling and the Origins of the Sensations of Itch and Pain

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Sci. Signal.  09 Aug 2011:
Vol. 4, Issue 185, pp. pe38
DOI: 10.1126/scisignal.2002353

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The skin is the largest sensory organ of the body. It is innervated by a diverse array of primary sensory neurons, including a heterogeneous subset of unmyelinated afferents called C fibers. C fibers, sometimes classified as nociceptors, can detect various painful stimuli, including temperature extremes. However, it is increasingly evident that these afferents respond to various pruritic stimuli and transmit information to the brain that is perceived as itch; this can subsequently drive scratching behavior. Although itch and pain are distinct sensations, they are closely related and can, under certain circumstances, antagonize each other. However, it is not clear precisely when, where, and how the processes generating these two sensations originate and how they are dissociated. Clues have come from the analysis of the activities of specific ligands and their receptors. New data indicate that specific pruritic ligands carrying both itch and pain information are selectively recognized by different G protein–coupled receptors (GPCRs), and this information may be transduced through different intracellular circuits in the same neuron. These findings raise questions about the intracellular mechanisms that preprocess and perhaps encode GPCR-mediated signals.

The sensation of itch is initiated by the activation of G protein–coupled receptors (GPCRs) in unmyelinated cutaneous C fibers emanating from cells located in the dorsal root ganglia (DRGs). The resulting electrochemical information, including stimulus intensity and location, is reported to the spinal cord and eventually to the brain. Various pruritic chemicals produce itch and scratching when injected or applied to the skin (1, 2) and also play a pivotal role in pain and hyperalgesia (increased sensitivity to pain) in inflamed tissues by exciting or sensitizing C-fiber nociceptors (1). These compounds include most proinflammatory molecules—such as endothelin-1, histamine, serotonin, and prostaglandins—for which there are corresponding well-characterized GPCRs. Based on the marked specificity of interaction between GPCRs and ligands, each pruritic chemical has been assumed to transmit itch and pain messages through the activation of the same cognate GPCR. Thus, it was thought that differentiation between itch and pain messages was likely to depend on cell types that are specialized as parts of neural circuits segregated for mediating itch or pain responses (3, 4). Alternatively, it has been suggested that pruritic compounds may produce complex response patterns in the skin, and the resultant “codes” may be processed and deciphered in the central nervous system to generate the sensations of itch or pain (3, 4).

The study by Liu et al. (5) focuses our thinking by providing new insights into how itch is dissociated from pain or hyperalgesia when pruritic chemicals are injected into the skin. Their findings point to the possibility that signals underlying multiple sensations emanating from the application of the same compound are separated at the first step in signaling. The agonist may be directly recognized by two different types of receptors in a small subset of C-fiber cutaneous nociceptors. One GPCR is responsible for mounting pain or pain-relevant signals; the other elicits the itch response and scratching. Liu et al.’s work further defines the specificity of the Mas-related G protein–coupled receptors (Mrgprs), an emerging family of GPCRs found in the DRGs and involved in the detection of different classes of pruritic ligands. These new findings provide another clue to understanding the complex relationship between itch and pain.

Protease-activated receptor 2 (PAR2) specifically responds to the synthetic peptide SLIGRL. When applied to skin, the peptide produces itch in human skin and scratching in mice (6, 7). In addition, activation of PAR2 elicits thermal and mechanical hyperalgesia by sensitizing transient receptor potential (TRP) channels such as TRPV1 or TRPA1 that directly recognize various painful stimuli (Fig. 1) (811). Thus, one long-standing view is that the peptide generates messages for both itch and pain through the activation of PAR2 expressed in sensory neurons. Liu et al. (5) found that SLIGRL could activate MrgprC11, a member of the Mrgpr family of receptors, in addition to PAR2. The cellular activity induced by the peptide, although dependent on the presence of MrgprC11, did not require the presence of PAR2. Furthermore, the in vivo behavioral response (scratching) also required MrgprC11. In contrast, the behavioral thermal hyperalgesic response was impaired in PAR2-deficient mice independent of the presence of MrgprC11. Consistent with this observation, application of SLIGRL to cultured DRG neurons appeared to sensitize the activity of TRPV1 through the action of PAR2 signaling. Liu et al. further studied the structure-activity relation of the agonist by creating a derivative of the SLIGRL peptide that activated PAR2, but not MrgprC11. When applied to the skin, the SLIGRL derivative could elicit the hyperalgesic response, but it no longer induced scratching activity. Taken together, these results elegantly demonstrate that MrgprC11 elicits itch, whereas PAR2 is responsible for the pain response (Fig. 1).

Fig. 1

Schematic signaling diagram of MrgprC11-containing neurons that process itch and pain signals. For example, the pruritic compound SLIGRL binds to two different GPCRs, PAR2 and MrgprC11, each of which may couple to distinct intracellular signal transduction pathways, leading to itch and thermal hyperalgesia, respectively. Note that MrgprC11- or MrgprA3-driven signaling is different from histamine-mediated itch sensation that requires PLCβ3 or phospholipase A2 (PLA2) to activate TRPV1 (27, 28). In contrast, TRPV1 and TRPA1 directly respond to noxious stimuli as indicated, causing pain sensation. In addition, the activity of these channels can be sensitized through Gαq-coupled GPCR-mediated intracellular signal transduction, which does not require direct activation of the channels before exposure to noxious or innocuous stimuli. PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; DAG


However, a number of unanswered questions remain. MrgprC11 is not exclusively activated by the SLIGRL peptide. Previous in vitro studies showed that MrgprC11 is relatively promiscuous with respect to ligand specificity and can be activated by other agonists that terminate with RF(Y) or its amidated form (12). These include γ2-melanocyte-stimulaing hormone, molluscan FMRFamides, mammalian neuropeptide FF, and bovine adrenal medulla peptides (BAM). Because many of these agonists have not been reported to evoke scratching, the question arises as to whether all agonists that activate MrgprC11 provoke scratching. If so, is MrgprC11 broadly tuned to detect various pruritic stimuli? If not, how does MrgprC11 selectively recognize pruritic compounds from other MrgprC11 agonists?

BAM 8-22, a proteolytic cleavage product of BAM, is an endogenous itch mediator acting on MrgprC11 or its human homolog, MrgprX1 (13, 14). However, BAM 8-22 appears to produce pain in addition to itch in humans (15). As with SLIGRL, it would be interesting to determine whether activation of MrgprC11 or MrgprX1 by BAM 8-22 selectively transduces an itch signal. If so, what is the receptor that senses the pain signal? Another question that remains to be answered is whether PAR2 is functionally active in primary sensory neurons. Both MrgprC11 and PAR2 are GPCRs, and their activation leads to intracellular signal transduction that includes a Gαq/11-PLCβ-Ca2+ pathway (Fig. 1). However, the SLIGRL-induced calcium response depends on the presence of MrgprC11 and not PAR2 in cultured DRG neurons, suggesting that PAR2 is not functional in these cells. Nevertheless, the observation that sensitization of TRPV1 activity requires the presence of PAR2 indicates that PAR2 signaling can still come into play in the response to SLIGRL. It is possible that the PAR2 receptor recruits a unique signal transduction circuit that is distinct from that of MrgprC11. Based on the overlapping distributions of MrgprC11 and PAR2, it is likely that each signaling pathway is “insulated” from the other to distinguish between stimuli in the same neuron. Indeed, this notion has garnered support from work (16) indicating that the pruritic activity of MrgprC11 and another Mrgpr family member, MrgprA3, requires activation of the TRPA1 channel rather than the TRPV1 channel and that the two receptors employ different signal transducing pathways to activate TRPA1 (Fig. 1). The paper by Liu et al. (5) implies the possibility that heterodimerization of receptors, complex formation between receptor and channel proteins, or the activation of other alternative intracellular signal transduction circuitry could provide a basis for the segregation of the PAR2 and MrgprC11 signaling pathways.

The solutions to some of the mysteries involved in the relationship between itch and pain may be found in the sensory cells that initiate these sensations. However, it is also possible that PAR2 signaling could be triggered in nonsensory neurons. Furthermore, PAR2 is also present on nonneuronal cells in skin, particularly keratinocytes (17). SLIGRL may activate PAR2 on keratinocytes or cells other than primary sensory afferents, releasing a different chemical mediator that acts on nearby sensory afferents through activation of receptors other than PAR2 or MrgprC11.

In mice, Mrgprs comprise a family of six single-copy genes (MrgD through H) as well as three subfamilies (MrgAs, MrgBs, and MrgC) (18). MrgprA3 is potently activated by chloroquine (CQ), an antimalarial drug, and CQ-induced itch requires the presence of MrgprA3 in mice (13). However, many of the Mrgprs remain orphan GPCRs whose functional role is not clear. It will be interesting to determine whether these orphan receptors provide the sensory neurons with molecular specificity, enabling them to discriminate among numerous pruritic ligands. Indeed, the molecular and cellular specificity of Mrgprs may provide a set of targets for the development of new anti-itch drugs, in particular for the treatment of chronic itch, an important clinical problem that has thus far remained relatively refractory to pharmacological intervention (19).

At the cellular level, it is important to note that MrgprC11-positive neurons are a very small subset of TRPV1-positive afferents (12, 13). The TRPV1-positive afferents are involved in heat-evoked pain as well as in responding to various pruritic chemicals, including the SLIGRL peptide (20, 21). TRPV1 afferents synapse to different types of spinal neurons that may be specialized not only for transmitting itch and pain, respectively, but also for regulating the itch response (2226). From the cellular perspective, therefore, understanding the function and anatomical organization of the MrgprC11- and TRPV1-positive population is necessary for a clear picture of the mechanisms that transmit or regulate itch and pain.


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