Nociceptors—Noxious Stimulus Detectors
2007; Cell Press; Volume: 55; Issue: 3 Linguagem: Inglês
10.1016/j.neuron.2007.07.016
ISSN1097-4199
Autores Tópico(s)Olfactory and Sensory Function Studies
ResumoClinical pain is a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. This review article is one of three reviews in this issue of Neuron that address our understanding of the pain process and possible solutions to the problem from both cellular- and systems-level viewpoints.In order to deal effectively with danger, it is imperative to know about it. This is what nociceptors do—these primary sensory neurons are specialized to detect intense stimuli and represent, therefore, the first line of defense against any potentially threatening or damaging environmental inputs. By sensing noxious stimuli and contributing to the necessary reactions to avoid them—rapid withdrawal and the experience of an intensely unpleasant or painful sensation, nociceptors are essential for the maintenance of the body's integrity. Although nociceptive pain is clearly an adaptive alarm system, persistent pain is maladaptive, essentially an ongoing false alarm. Here, we highlight the genesis of nociceptors during development and the intrinsic properties of nociceptors that enable them to transduce, conduct, and transmit nociceptive information and also discuss how their phenotypic plasticity contributes to clinical pain. Clinical pain is a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. This review article is one of three reviews in this issue of Neuron that address our understanding of the pain process and possible solutions to the problem from both cellular- and systems-level viewpoints. In order to deal effectively with danger, it is imperative to know about it. This is what nociceptors do—these primary sensory neurons are specialized to detect intense stimuli and represent, therefore, the first line of defense against any potentially threatening or damaging environmental inputs. By sensing noxious stimuli and contributing to the necessary reactions to avoid them—rapid withdrawal and the experience of an intensely unpleasant or painful sensation, nociceptors are essential for the maintenance of the body's integrity. Although nociceptive pain is clearly an adaptive alarm system, persistent pain is maladaptive, essentially an ongoing false alarm. Here, we highlight the genesis of nociceptors during development and the intrinsic properties of nociceptors that enable them to transduce, conduct, and transmit nociceptive information and also discuss how their phenotypic plasticity contributes to clinical pain. As a result of physiological experiments he conducted at the dawn of the 20th century, Charles Sherrington concluded, “There is considerable evidence that the skin is provided with a set of nerve endings whose specific office it is to be amenable to stimuli that do the skin injury, stimuli that in continuing to act would injure it still further” (Sherrington, 1903Sherrington C.S. Qualitative differences of spinal reflex corresponding with qualitative difference of cutaneous stimulus.J. Physiol. 1903; 30: 39-46Crossref PubMed Google Scholar). He further stated that since “harmfulness is the characteristic of the stimuli by which [the nerve endings] are provocable…for physiological reference therefore they are preferably termed nocicipient” (Sherrington, 1903Sherrington C.S. Qualitative differences of spinal reflex corresponding with qualitative difference of cutaneous stimulus.J. Physiol. 1903; 30: 39-46Crossref PubMed Google Scholar). A few years later Sherrington expanded his definition of a noxious stimulus as one with an intensity and quality sufficient to trigger reflex withdrawal, autonomic responses, and pain, collectively constituting what he called the nociceptive reaction. He also redefined the neural apparatus responsible for detecting a noxious stimulus as nociceptive nerves or nociceptors (Sherrington, 1906Sherrington C.S. The Integrative Action of the Nervous System. Scribner, New York1906Google Scholar). Implicit in this new term, coined 100 years ago, was that pain is a specific sensation with its own sensory machinery. This view was something that Descartes and von Frey had also argued in favor of, although in rather different ways. Sherrington's notion was directly counter to then widely held theories that pain resulted from a central summation in response to excessive sensory stimulation or that all nerve endings are similar and that certain patterns of activity produced by intense stimulation evoke pain. Fundamentally, this divergence reflected the competing specificity and pattern theories of pain that characterized much of 19th and early 20th century pain sensory biology. The debate reached a climax in the 1960s and 70s with Ed Perl arguing vigorously that pain is mediated by specialized high-threshold nociceptor sensory neurons (Bessou and Perl, 1969Bessou P. Perl E.R. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli.J. Neurophysiol. 1969; 32: 1025-1043PubMed Google Scholar), and Pat Wall and Ron Melzack emphatically emphasizing central processing as generating pain (Melzack and Wall, 1965Melzack R. Wall P.D. Pain mechanisms: a new theory.Science. 1965; 150: 971-979Crossref PubMed Google Scholar). It is now clear that this clash of the sensory titans was quite artificial. It is not an either/or situation; nociceptors are indeed the peripheral path to nociceptive pain, and altered central processing does contribute to pain hypersensitivity in patients. We can, however, now quietly relegate the view that sensory specificity is encoded by activity in nonspecialized primary sensory neurons to the garbage can of history and instead loudly celebrate the first century of the nociceptor, a specialized noxious stimulus detector. We also increasingly recognize that the nociceptor is highly modifiable in response to injury of its axon and on exposure to inflammation and that this plasticity is integral to its pain-generating functions and may reflect, moreover, a recapitulation of the signaling that determines its differentiation during development. In interacting with the environment, living organisms have to recognize and react to harmful stimuli to avoid them. To do this, nociceptors have a high threshold and normally respond, as Sherrington clearly recognized, only to stimuli of sufficient energy to potentially or actually damage tissue. Some nociceptors are thinly myelinated (Aδ-fibers) but most are unmyelinated (C fibers), and these slowly conducting afferents represent the majority of sensory neurons in the peripheral nervous system. Like all primary sensory neurons in the somatosensory system, they have their cell bodies in dorsal root or trigeminal ganglia, give rise to a single axon that bifurcates into a peripheral branch that innervates peripheral target tissue, and a central axon that enters the CNS to synapse on nociceptive second order neurons. The nociceptor in consequence has four major functional components, the peripheral terminal that transduces external stimuli and initiates action potentials, the axon that conducts action potentials, the cell body that controls the identity and integrity of the neuron, and the central terminal which forms the presynaptic element of the first synapse in the sensory pathway in the CNS (Figure 1). In addition to the contribution of the intrinsic properties of the neuron to its functional role, crucial too are the extrinsic signals that feed onto the neuron from targets, nerves, and the spinal cord that can produce profound phenotypic alterations. Loss of nociceptor neurons in patients with hereditary sensory and autonomic neuropathy type 4, due to mutations in the nerve growth factor (NGF) TrkA receptor that result in a failure of nociceptor survival in the embryo (Verpoorten et al., 2006Verpoorten N. Claeys K.G. Deprez L. Jacobs A. Van G.V. Lagae L. Arts W.F. De Meirleir L. Keymolen K. Ceuterick-de Groote C. De Jonghe P. et al.Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV.Neuromuscul. Disord. 2006; 16: 19-25Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar), produces congenital pain hyposensitivity, and starkly reveals the importance of nociceptors as an early warning device. These unfortunate individuals burn and chew their tongues and lips, and as a result of undetected damage, lose the tips of their fingers and damage joints. Ignorance of noxious stimuli is not bliss. A congenital indifference to pain without loss of nociceptor neurons has been shown recently to occur with loss of function mutations in the SCN9A gene encoding the alpha subunit of Nav1.7 voltage-gated sodium channel (Cox et al., 2006Cox J.J. Reimann F. Nicholas A.K. Thornton G. Roberts E. Springell K. Karbani G. Jafri H. Mannan J. Raashid Y. et al.An SCN9A channelopathy causes congenital inability to experience pain.Nature. 2006; 444: 894-898Crossref PubMed Scopus (501) Google Scholar, Goldberg et al., 2007Goldberg Y.P. MacFarlane J. MacDonald M.L. Thompson J. Dube M.P. Mattice M. Fraser R. Young C. Hossain S. Pape T. et al.Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.Clin. Genet. 2007; 71: 311-319Crossref PubMed Scopus (165) Google Scholar). In this review, we highlight recent insights into how nociceptors differentiate from progenitors during development to achieve the specialized nociceptor molecular phenotype, how they transduce noxious stimuli and transfer input to the CNS, and how some of the adaptive and maladaptive functional and phenotypic changes that occur in nociceptors produce spontaneous pain and pain hypersensitivity. Nociceptors develop from those neural crest stem cells that migrate from the dorsal part of the neural tube and form late during neurogenesis, whereas neurons born earlier become proprioceptors or low-threshold mechanoceptors (Anderson, 2000Anderson D.J. Genes, lineages and the neural crest: a speculative review.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2000; 355: 953-964Crossref PubMed Google Scholar, Fitzgerald, 2005Fitzgerald M. The development of nociceptive circuits.Nat. Rev. Neurosci. 2005; 6: 507-520Crossref PubMed Scopus (307) Google Scholar, Lawson and Biscoe, 1979Lawson S.N. Biscoe T.J. Development of mouse dorsal root ganglia: an autoradiographic and quantitative study.J. Neurocytol. 1979; 8: 265-274Crossref PubMed Google Scholar, Marmigere and Ernfors, 2007Marmigere F. Ernfors P. Specification and connectivity of neuronal subtypes in the sensory lineage.Nat. Rev. Neurosci. 2007; 8: 114-127Crossref PubMed Scopus (148) Google Scholar). All newly formed embryonic nociceptors express the TrkA nerve growth factor receptor (Marmigere and Ernfors, 2007Marmigere F. Ernfors P. Specification and connectivity of neuronal subtypes in the sensory lineage.Nat. Rev. Neurosci. 2007; 8: 114-127Crossref PubMed Scopus (148) Google Scholar). However, the transcription factors that determine nociceptor cell fate remain unclear. Formation of most TrkA+ neurons is dependent on the proneural transcription factor Neurogenin1 (Ngn1) (Ma et al., 1998Ma Q. Chen Z. del Barco Barrentes I. de la Pompa J.L. Anderson D.J. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia.Neuron. 1998; 20: 469-482Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar, Ma et al., 1999Ma Q. Fode C. Guillemot F. Anderson D.J. Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia.Genes Dev. 1999; 13: 1717-1728Crossref PubMed Google Scholar). Ngn1 activity is, however, not specific for nociceptors—it's also required for formation of TrkB+ and TrkC+ low-threshold mechanoceptors (Ma et al., 1998Ma Q. Chen Z. del Barco Barrentes I. de la Pompa J.L. Anderson D.J. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia.Neuron. 1998; 20: 469-482Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar, Ma et al., 1999Ma Q. Fode C. Guillemot F. Anderson D.J. Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia.Genes Dev. 1999; 13: 1717-1728Crossref PubMed Google Scholar). The homeobox gene Brn3a and the zinc finger gene Klf7 are required for the maintenance, but not the initiation of TrkA expression, but these transcription factors are also like Ngn1, expressed in both developing nociceptors and nonnociceptors (Lei et al., 2006Lei L. Zhou J. Lin L. Parada L.F. Brn3a and Klf7 cooperate to control TrkA expression in sensory neurons.Dev. Biol. 2006; 300: 758-769Crossref PubMed Scopus (16) Google Scholar). The Runx1 runt domain transcription factor is however, expressed exclusively in TrkA+ neurons at early embryonic stages (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, Kramer et al., 2006Kramer I. Sigrist M. de Nooij J.C. Taniuchi I. Jessell T.M. Arber S. A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.Neuron. 2006; 49: 379-393Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, Levanon et al., 2002Levanon D. Bettoun D. Harris-Cerruti C. Woolf E. Negreanu V. Eilam R. Bernstein Y. Goldenberg D. Xiao C. Fliegauf M. et al.The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons.EMBO J. 2002; 21: 3454-3463Crossref PubMed Scopus (257) Google Scholar, Marmigere et al., 2006Marmigere F. Montelius A. Wegner M. Groner Y. Reichardt L.F. Ernfors P. The Runx1/AML1 transcription factor selectively regulates development and survival of TrkA nociceptive sensory neurons.Nat. Neurosci. 2006; 9: 180-187Crossref PubMed Scopus (76) Google Scholar, Theriault et al., 2005Theriault F.M. Nuthall H.N. Dong Z. Lo R. Barnabe-Heider F. Miller F.D. Stifani S. Role for Runx1 in the proliferation and neuronal differentiation of selected progenitor cells in the mammalian nervous system.J. Neurosci. 2005; 25: 2050-2061Crossref PubMed Scopus (66) Google Scholar, Yoshikawa et al., 2007Yoshikawa M. Senzaki K. Yokomizo T. Takahashi S. Ozaki S. Shiga T. Runx1 selectively regulates cell fate specification and axonal projections of dorsal root ganglion neurons.Dev. Biol. 2007; 303: 663-674Crossref PubMed Scopus (38) Google Scholar), but because its expression is initiated some time after the onset of TrkA expression, it is unlikely to be involved in early nociceptor cell fate determination (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Following sensory neurogenesis, prospective nociceptors undergo two distinct differentiation pathways that lead to the formation of two major classes of nociceptors, peptidergic and nonpeptidergic nociceptors. These two sets of nociceptors express distinct repertoires of ion channels and receptors and innervate distinct peripheral and central targets (Braz et al., 2005Braz J.M. Nassar M.A. Wood J.N. Basbaum A.I. Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor.Neuron. 2005; 47: 787-793Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, Snider and McMahon, 1998Snider W.D. McMahon S.B. Tackling pain at the source: new ideas about nociceptors.Neuron. 1998; 20: 629-632Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar, Zylka et al., 2005Zylka M.J. Rice F.L. Anderson D.J. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd.Neuron. 2005; 45: 17-25Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). During the perinatal and postnatal period, about half of developing nociceptors switch off TrkA and begin to express Ret, the transmembrane signaling component of the receptor for glial cell-derived growth factor (GDNF) and other GDNF-related growth factors. These neurons become the nonpeptidergic nociceptors, most of which bind isolectin B4 (IB4+). The remaining nociceptors retain TrkA (a few also coexpress Ret) and develop into the peptidergic class of nociceptors that express CGRP and SP and do not bind IB4 (IB4−) (Bennett et al., 1996Bennett D.L.H. Averill S. Priestley J.V. McMahon S.B. Postnatal changes in the expression of trkA high affinity NGF receptor in primary sensory neurones.Eur. J. Neurosci. 1996; 8: 2204-2208Crossref PubMed Scopus (114) Google Scholar, Molliver et al., 1997Molliver D.C. Wright D.E. Leitner M.L. Parsadanian A.S. Doster K. Wen D. Yan Q. Snider W.D. IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.Neuron. 1997; 19: 849-861Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar). The dynamic expression of Runx1 appears to be an important player in this process (Figure 2; Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, Kramer et al., 2006Kramer I. Sigrist M. de Nooij J.C. Taniuchi I. Jessell T.M. Arber S. A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.Neuron. 2006; 49: 379-393Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, Yoshikawa et al., 2007Yoshikawa M. Senzaki K. Yokomizo T. Takahashi S. Ozaki S. Shiga T. Runx1 selectively regulates cell fate specification and axonal projections of dorsal root ganglion neurons.Dev. Biol. 2007; 303: 663-674Crossref PubMed Scopus (38) Google Scholar). Early embryonic nociceptors share a similar molecular identity, coexpressing both TrkA and Runx1 (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). During the period when nociceptor segregation occurs, Runx1's expression is extinguished in prospective TrkA+ peptidergic cells but persists in nonpeptidergic neurons (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Conditional knockout of Runx1 in the DRG transforms these nonpeptidergic cells to a TrkA+ CGRP+ identity, and in this situation most nociceptors develop as peptidergic nociceptors (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, Yoshikawa et al., 2007Yoshikawa M. Senzaki K. Yokomizo T. Takahashi S. Ozaki S. Shiga T. Runx1 selectively regulates cell fate specification and axonal projections of dorsal root ganglion neurons.Dev. Biol. 2007; 303: 663-674Crossref PubMed Scopus (38) Google Scholar). Conversely, constitutive expression of Runx1 in all nociceptors is sufficient to suppress embryonic peptidergic differentiation (Kramer et al., 2006Kramer I. Sigrist M. de Nooij J.C. Taniuchi I. Jessell T.M. Arber S. A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.Neuron. 2006; 49: 379-393Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Runx1 also coordinates afferent targeting to the spinal cord; in mice that lack Runx1 prospective IB4+ nonpeptidergic afferents adopt the projection pattern typical of peptidergic afferents (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). These observations suggest that persistent Runx1 expression promotes the Ret+ nonpeptidergic cell fate, whereas loss of Runx1 is essential for peptidergic differentiation. (A) Progressive segregation of peptidergic versus nonpeptidergic nociceptors. Note that Runx1 expression is extinguished in prospective TrkA+ peptidergic neurons, but the signals that trigger Runx1 downregulation in these neurons remain elusive (“?”). (B) An interaction network that controls expression of nociceptor-specific molecules. The purple arrow indicates that TrkA signaling is required to maintain Runx1 expression at perinatal stages, but it remains unknown if TrkA signaling is directly involved in this process. The signals that control the initiation of Runx1 expression are also unknown (“??”). The dashed arrow indicates possibility that Runx1 has a direct role in controlling expression of TRPA1, MrgA1, A3 and B4, although Runx1 could activate these genes by regulating Ret. Several recent studies suggest that Runx1 and TrkA/Ret signaling pathways form a complex interaction loop for establishing nonpeptidergic nociceptor cell fate (Ibanez and Ernfors, 2007Ibanez C.F. Ernfors P. Hierarchical control of sensory neuron development by neurotrophic factors.Neuron. 2007; 54: 673-675Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ; Luo et al., 2007Luo W. Wickramasinghe S.R. Savitt J.M. Griffin J.W. Dawson T.M. Ginty D.D. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons.Neuron. 2007; 54: 739-754Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). TrkA-signaling is required to activate Ret, partly it appears by maintaining Runx1 expression at perinatal stages (Luo et al., 2007Luo W. Wickramasinghe S.R. Savitt J.M. Griffin J.W. Dawson T.M. Ginty D.D. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons.Neuron. 2007; 54: 739-754Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Raf kinases acting downstream of TrkA or other signaling molecules are required to maintain Ret expression by controlling expression of the Runx1 cofactor protein, CBF-β (Zhong et al., 2006Zhong J. Pevny L. Snider W.D. “Runx”ing towards sensory differentiation.Neuron. 2006; 49: 325-327Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Finally, Ret signaling acts to suppress TrkA expression in prospective nonpeptidergic neurons (Luo et al., 2007Luo W. Wickramasinghe S.R. Savitt J.M. Griffin J.W. Dawson T.M. Ginty D.D. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons.Neuron. 2007; 54: 739-754Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar; Figure 2). However, despite progress in teasing out the determinants of nociceptor specification, several issues remain to be resolved. Because both TrkA and Ret are required for afferents to innervate peripheral targets (Luo et al., 2007Luo W. Wickramasinghe S.R. Savitt J.M. Griffin J.W. Dawson T.M. Ginty D.D. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons.Neuron. 2007; 54: 739-754Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, Patel et al., 2000Patel T.D. Jackman A. Rice F.L. Kucera J. Snider W.D. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo.Neuron. 2000; 25: 345-357Abstract Full Text Full Text PDF PubMed Google Scholar), a loss of either TrkA or Ret signaling prevents nociceptors from receiving other target-derived signals. Consequently, it is not known if TrkA signaling directly or indirectly controls expression of Runx1, CBF-β, and Ret, or if Ret signaling is directly involved in TrkA suppression. In addition, while TrkA signaling is required to maintain Runx1 expression at embryonic stages, Runx1 expression is extinguished from TrkA+ peptidergic nociceptors during perinatal/postnatal development, and we need to determine, therefore, if TrkA signaling switches from activating to suppressing Runx1 expression at different developmental stages or if a peripheral innervation defect in the absence of TrkA signaling indirectly extinguishes Runx1 expression. A further problem is that the intrinsic transcription factors that establish peptidergic nociceptor cell fate still remain elusive. Although Runx1 suppresses TrkA expression during postnatal development (Chen et al., 2006Chen C.L. Broom D.C. Liu Y. de Nooij J.C. Li Z. Cen C. Samad O.A. Jessell T.M. Woolf C.J. Ma Q. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.Neuron. 2006; 49: 365-377Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar), it is capable of activating TrkA expression after ectopic expression in the neural tube and migratory neural crest cells (Marmigere et al., 2006Marmigere F. Montelius A. Wegner M. Groner Y. Reichardt L.F. Ernfors P. The Runx1/AML1 transcription factor selectively regulates development and survival of TrkA nociceptive sensory neurons.Nat. Neurosci. 2006; 9: 180-187Crossref PubMed Scopus (76) Google Scholar). Runx1 can, therefore, exert opposing activities depending on the cellular context. It will be extremely interesting to establish if changes in context-dependent transcriptional activities contribute to the phenotypic switches in nociceptors that occur in pathological conditions (see below). The mature nociceptor expresses dozens of ion channels and receptors, and the correct establishment of their expression is essential for nociceptors to detect specific noxious stimuli (see below, “The Differentiated Nociceptor”). There are two notable features about the developmental control of sensory channels/receptor expression. First, many sensory channels/receptors are expressed in only a partially overlapping or mutually exclusive manner, including TRP class thermal/chemical receptors and Mrg class G protein-coupled receptors (Dong et al., 2001Dong X. Han S. Zylka M.J. Simon M.I. Anderson D.J. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.Cell. 2001; 106: 619-632Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Hjerling-Leffler et al., 2007Hjerling-Leffler J. Alqatari M. Ernfors P. Koltzenburg M. Emergence of functional sensory subtypes as defined by transient receptor potential channel expression.J. Neurosci. 2007; 27: 2435-2443Crossref PubMed Scopus (91) Google Scholar, Story et al., 2003Story G.M. Peier A.M. Reeve A.J. Eid S.R. Mosbacher J. Hricik T.R. Earley T.J. Hergarden A.C. Andersson D.A. Hwang S.W. et al.ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.Cell. 2003; 112: 819-829Abstract Full Text Full Text PDF PubMed Scopus (1079) Google Scholar, Zylka et al., 2003Zylka M.J. Dong X. Southwell A.L. Anderson D.J. Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family.Proc. Natl. Acad. Sci. USA. 2003; 100: 10043-10048Crossref PubMed Scopus (100) Google Scholar). Second, the emergence of individual sensory channels/receptors is subject to complex temporal control. For example, expression of three TRP channels, TRPV1, TRPM8, and TRPA1, is initiated at E12.5, E16.5, and P0, respectively (Hjerling-Leffler et al., 2007Hjerling-Leffler J. Alqatari M. Ernfors P. Koltzenburg M. Emergence of functional sensory subtypes as defined by transient receptor potential channel expression.J. Neurosci. 2007; 27: 2435-2443Crossref PubMed Scopus (91) Google Scholar), while TRPA1 expression in peptidergic nociceptors is established at P0 and nonpeptidergic nociceptors at P14, respectively (Hjerling-Leffler et al., 2007Hjerling-Leffler J. Alqatari M. Ernfors P. Koltzenburg M. Emergence of functional sensory subtypes as defined by transient receptor potential channel expression.J. Neurosci. 2007; 27: 2435-2443Crossref PubMed Scopus (91) Google Scholar). The complex expression pattern of sensory channels and receptors is established through a series of hierarchical controls. TrkA signaling is required to establish the molecular and functional identity of nociceptors (Lewin, 1996Lewin G.R. Neurotrophins and the specification of neuronal phenotype.Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996; 351: 405-411Crossref PubMed Google Scholar, Luo et al., 2007Luo W. Wickramasinghe S.R. Savitt J.M. Griffin J.W. Dawson T.M. Ginty D.D. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpep
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