ReviewNucleotide signaling and cutaneous mechanisms of pain transduction
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.
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