Review
Nucleotide signaling and cutaneous mechanisms of pain transduction

https://doi.org/10.1016/j.brainresrev.2008.12.013Get rights and content

Abstract

Sensory neurons that innervate the skin provide critical information about physical contact between the organism and the environment, including information about potentially-damaging stimuli that give rise to the sensation of pain. These afferents also contribute to the maintenance of tissue homeostasis, inflammation and wound healing, while sensitization of sensory afferents after injury results in painful hypersensitivity and protective behavior. In contrast to the traditional view of primary afferent terminals as the sole site of sensory transduction, recent reports have lead to the intriguing idea that cells of the skin play an active role in the transduction of sensory stimuli. The search for molecules that transduce different types of sensory stimuli (mechanical, heat, chemical) at the axon terminal has yielded a wide range of potential effectors, many of which are expressed by keratinocytes as well as neurons. Emerging evidence underscores the importance of nucleotide signaling through P2X ionotropic and P2Y metabotropic receptors in pain processing, and implicates nucleotide signaling as a critical form of communication between cells of the skin, immune cells and sensory neurons. It is of great interest to determine whether pathological changes in these mechanisms contribute to chronic pain in human disease states such as complex regional pain syndrome (CRPS). This review discusses recent advances in our understanding of communication mechanisms between cells of the skin and sensory axons in the transduction of sensory input leading to pain.

Introduction

The skin is a complex laminar tissue that serves both as a protective barrier and as the body's largest sensory organ. As the site of contact for the organism with the external environment, it provides essential information about external stimuli, including those with the potential to cause tissue damage. The outer region of the skin, the epidermis, is extensively innervated by axons arising from sensory neurons of the dorsal root (DRG) and trigeminal ganglia, which convey sensory input to the central nervous system. These sensory afferents are intimately associated with keratinocytes, mast cells and Langerhans cells, indicating the capacity of peripheral sensory endings to monitor the ongoing status of the skin as well as the activation state of cells involved in immune vigilance (Hosoi et al., 1993, Gaudillere et al., 1996, Shepherd et al., 2005, Boulais and Misery, 2008). Signaling processes in keratinocytes have been investigated largely from the perspective of mechanisms involved in intrinsic homeostatic functions of the epidermis, such as differentiation, metabolism and wound repair. However, several lines of evidence indicate a complex system of communication between skin cells and the sensory afferents innervating the skin. Indeed, keratinocytes express many proteins more commonly associated with neuronal function, most notably receptors implicated in the transduction of sensory stimuli such as the TRP family of temperature-sensitive cation channels (Peier et al., 2002;Chung et al., 2004, Stander et al., 2004). Additionally, keratinocytes release numerous factors that activate sensory neurons, including cytokines, neuropeptides and nucleotides (Burrell et al., 2005, Zhao et al., 2008). They also secrete neurotrophic factors that support axon arborization and maintain functional properties of sensory neurons (Albers and Davis, 2007). Keratinocytes thus contain signaling machinery capable of detecting many forms of noxious and non-noxious stimuli and communicating these stimuli to sensory afferents (Fig. 1). Conversely, sensory endings are not merely sensory-transducing structures but also play an active efferent role in the skin, releasing pro-inflammatory neuropeptides and other factors (including ATP) that contribute to inflammation, edema, wound healing and tissue homeostasis (Holzer, 1988, Dalsgaard et al., 1989, Roosterman et al., 2006). Wound healing is significantly compromised in denervated tissue, underscoring the bi-directional nature of skin-nerve communication (Gibran et al., 2002, Barker et al., 2006). This review addresses emerging evidence that keratinocytes may be active players in the transduction of noxious sensory stimuli, and that nucleotides may represent a key class of messengers conveying information from skin cells to cutaneous axon terminals (Denda et al., 2007).

Persistent pain originating in the skin occurs following numerous pathological conditions, including traumatic injury (including postoperative pain), burn injuries (which cause extreme persistent pain and have unique pathological features), and neuropathic pain, including acute zoster (i.e., shingles), postherpetic neuralgia, and complex regional pain syndrome (CRPS) as well as diabetic, chemotherapeutic and AIDS-related neuropathies. In addition, a wide variety of pathological conditions cause persistent itch (a sensation unique to skin) that can significantly impair quality of life (Binder et al., 2008). Both neuropathic and burn pain are often intractable to opiate analgesia within limitations imposed by the potential for severe side effects, such as respiratory and peristaltic depression. Patients often resort to a variety of alternative therapies (e.g. hypnosis) to achieve pain relief, but controlled demonstrations of efficacy for alternative pain treatments are limited (Ohrbach et al., 1998;Gallagher et al., 2000). In patients suffering from neuropathic pain syndromes, spontaneous burning pain, dysesthesias, lancinating and shooting pains, thermal hyperalgesia and mechanical allodynia of the skin are persistent problems that can be extremely intense and very difficult to control (Dworkin and Portenoy, 1996;Panlilio et al., 2002;Rowbotham, 2006;Ziegler, 2006;Said, 2007;Wong et al., 2007). The mechanisms that drive cutaneous pain are poorly understood and the extent to which peripheral mechanisms contribute to neuropathic pain is still under debate, making it difficult to develop mechanism-based therapies or to identify appropriate strategies for treatment.

Section snippets

Roles for nucleotides and their receptors in signaling pain

ATP has been studied for more than 30 years as a candidate messenger of tissue damage (Collier et al., 1966). Evidence that other nucleotides (e.g. ADP, UTP) might also contribute to nociception (signal transduction leading to the sensation of pain) has recently begun to emerge (Molliver et al., 2002, Sanada et al., 2002). ATP injected into the skin causes moderate pain that becomes intense when the skin is inflamed (Bleehen and Keele, 1977, Hamilton et al., 2000). After demonstrating the

Mas-related G-protein coupled receptors as genetic markers for nociceptors

In 2001, David Anderson's laboratory at Caltech published data on the cloning of a new family of G-protein coupled receptors termed mas-related g protein-coupled receptors (Mrg or Mrgpr) (Dong et al., 2001). This family was made up of over 50 members in mice, and individual members were found to be selectively expressed in anatomically-distinct subsets of sensory neurons of the dorsal root and trigeminal ganglia (DRG and TG). These receptors respond to diverse ligands such as adenine,

Role for P2X3 in thermal sensation

The mechanisms by which P2X3 participates in thermal sensation have yet to be resolved. However, the unusual desensitization kinetics of P2X3 may provide an answer. During application of ATP this channel generates currents that completely desensitize within 1 s and can take longer than 20 min to recover from desensitization (Sokolova et al., 2004;Pratt et al., 2005;Khmyz et al., 2008). This suggests that the continued responsiveness to ATP of P2X3-expressing neurons is limited by the time

Functional stratification of the skin

As noted above, the process of epidermal sensory transduction likely includes stimulus-induced release of ligands such as ATP from keratinocytes that may in turn activate epidermal sensory endings such as those that express nucleotide receptors. Importantly, recent evidence indicates that the epidermis and its sensory endings are morphologically and chemically organized into a stratified sensory transducing and integrating organ (Fundin et al., 1997, Khodorova et al., 2003, Ibrahim et al., 2005

Cutaneous-neuro-immune interactions in CRPS

Pioneering neurologist S. Weir Mitchell and colleagues first described an unusual phenotype in detailed case histories of American Civil War soldier with penetrating sword and bullet wounds (Mitchell, 1864). Their descriptions of “causalgia” documented the salient symptoms of excessively severe and prolonged chronic pain while at rest and hyperalgesia (excess pain after sensory stimulation) in an arm or leg distal to the site of a nerve or plexus injury. They identified the symptoms of

Summary

Evidence is accumulating that communication between the skin and primary sensory neurons through nucleotide signaling provides a mechanism for the transduction of nociceptive stimuli. This hypothesis is based on the following findings: 1) skin cells express a variety of receptors known to participate in pain signaling; 2) skin cells can release numerous pain-related molecules, including ATP; 3) cutaneous nociceptors are responsive to substances released by skin cells, particularly ATP and its

Acknowledgments

Supported by: ALO: the Public Health Service (R01NS42866, K24NS059892), the Reflex Sympathetic Dystrophy Syndrome Association and the National Organization for Rare Disorders. DCM: NIH NS056122.

References (117)

  • DendaM. et al.

    P2X purinergic receptor antagonist accelerates skin barrier repair and prevents epidermal hyperplasia induced by skin barrier disruption

    J. Invest. Dermatol.

    (2002)
  • DongX. et al.

    A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons

    Cell

    (2001)
  • DworkinR.H. et al.

    Pain and its persistence in herpes zoster

    Pain

    (1996)
  • GibranN.S. et al.

    Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus

    J. Surg. Res.

    (2002)
  • GreigA.V. et al.

    Purinergic receptors are part of a signaling system for keratinocyte proliferation, differentiation, and apoptosis in human fetal epidermis

    J. Invest. Dermatol.

    (2003)
  • HolzerP.

    Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

    Neuroscience

    (1988)
  • KoerberH.R. et al.

    Comprehensive phenotyping of sensory neurons using an ex vivo somatosensory system

    Physiol. Behav.

    (2002)
  • LawandN.B. et al.

    Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats

    Eur. J. Pharmacol.

    (1997)
  • LawsonJ.J. et al.

    TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat

    J. Pain

    (2008)
  • LuJ. et al.

    Small primary sensory neurons innervating epidermis and viscera display differential phenotype in the adult rat

    Neurosci. Res.

    (2001)
  • MalinS.A. et al.

    Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y(2)

    Pain

    (2008)
  • O'BrienC. et al.

    Differences in the chemical expression of rat primary afferent neurons which innervate skin, muscle or joint

    Neuroscience

    (1989)
  • OaklanderA.L. et al.

    Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy)

    Pain

    (2006)
  • SanadaM. et al.

    Increase in intracellular Ca(2+) and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons

    Neuroscience

    (2002)
  • SniderW.D. et al.

    Tackling pain at the source: new ideas about nociceptors

    Neuron

    (1998)
  • AlbersK.M. et al.

    The skin as a neurotrophic organ

    Neuroscientist

    (2007)
  • BalonovK. et al.

    Tactile allodynia initiated by local subcutaneous endothelin-1 is prolonged by activation of TRPV-1 receptors

    Exp. Biol. Med.

    (2006)
  • BarkerA.R. et al.

    Wound healing in denervated tissue

    Ann. Plast. Surg.

    (2006)
  • BelleM.D. et al.

    Characterization of a thy1.2 GFP transgenic mouse reveals a tissue-specific organization of the spinal dorsal horn

    Genesis

    (2007)
  • Bender, E., Buist, A., Jurzak, M., Langlois, X., Baggerman, G., Verhasselt, P., Ercken, M., Guo, H.Q., Wintmolders, C.,...
  • BinderA. et al.

    Disease mechanisms in neuropathic itch

    Nat. Clin. Pract. Neurol.

    (2008)
  • BodinP. et al.

    Purinergic signalling: ATP release

    Neurochem. Res.

    (2001)
  • BoulaisN. et al.

    The epidermis: a sensory tissue

    Eur. J. Dermatol.

    (2008)
  • BurnstockG.

    Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction

    J. Anat.

    (1999)
  • ChenC.C. et al.

    A P2X purinoceptor expressed by a subset of sensory neurons

    Nature

    (1995)
  • CockayneD.A. et al.

    Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice

    Nature

    (2000)
  • CockayneD.A. et al.

    P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP

    J. Physiol.

    (2005)
  • CollierH.O. et al.

    Antagonism by aspirin and fenamates of bronchoconstriction and nociception induced by adenosine-5′-triphosphate

    Nature

    (1966)
  • Dai, Y., Fukuoka, T., Wang, H., Yamanaka, H., Obata, K., Tokunaga, A., Noguchi, K., 2004. Contribution of sensitized...
  • DalsgaardC.J. et al.

    Calcitonin gene-related peptide-like immunoreactivity in nerve fibers in the human skin. Relation to fibers containing substance P-, somatostatin-and vasocactive intestinalpolypeptide-like immunoreactivity

    Histochemistry

    (1989)
  • DendaM. et al.

    Epidermal keratinocytes as the forefront of the sensory system

    Exp. Dermatol.

    (2007)
  • DixonC.J. et al.

    Regulation of epidermal homeostasis through P2Y2 receptors

    Br. J. Pharmacol.

    (1999)
  • Donnelly-RobertsD. et al.

    Painful purinergic receptors

    J. Pharmacol. Exp. Ther.

    (2008)
  • DussorG. et al.

    Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors

    J. Neurophysiol.

    (2008)
  • EganC.L. et al.

    Characterization of unmyelinated axons uniting epidermal and dermal immune cells in primate and murine skin

    J. Cutan. Pathol.

    (1998)
  • EvansJ.A.

    Reflex sympathetic dystrophy

    Surg. Gynecol. Obstet.

    (1946)
  • FundinB.T. et al.

    Comprehensive immunofluorescence and lectin binding analysis of intervibrissal fur innervation in the mystacial pad of the rat

    J. Comp. Neurol.

    (1997)
  • GallagherG. et al.

    Treatment of pain in severe burns

    Am. J. Clin. Dermatol.

    (2000)
  • GaliettaL.J. et al.

    Characterization of chloride and cation channels in cultured human keratinocytes

    Pflugers Arch.

    (1991)
  • GaudillereA. et al.

    Intimate associations between PGP9.5-positive nerve fibres and Langerhans cells

    Br. J. Dermatol.

    (1996)
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