Nucleotide signaling and cutaneous mechanisms of pain transduction

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.

In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans

“…Equally important is the lack of specific evidence as to whether these receptors and their signaling pathways are contained within the CMH neuron itself or occur instead, or in addition, in other neurons or even nonneuronal cells. For example, keratinocytes contain TRPV1 receptors (Stander et al 2004), protease-activated receptors (Steinhoff et al 1999), and histamine receptors (Yamaura et al 2009) that when activated may lead to the release of chemicals (Dussor et al 2009) that activate or modulate the responses of CMH and other sensory neurons. In support of a possible role of other cell types, the cell bodies of CMH neurons are not immunopositive for TRPV1 (Lawson et al 2008).…”

Labeled lines meet and talk: population coding of somatic sensations

“…Interestingly, TRPV3 is expressed in both DRG neurons and keratinocytes in humans, but only in keratinocytes in mice (58). In response to warmth and heat, keratinocytes may release chemicals such as UTP and ATP, which in turn activate P2X and P2Y receptors in skin nerve terminals (58)(59)(60)(61). For example, P2Y2 is a receptor of UTP, and its expression in mouse DRG neurons is required for proper heat sensation (62).…”

“…Most CMH neurons in mice can be marked by the expression of the G protein-coupled receptor Mrgprd, and these neurons coexpressed P2X3 (53,(64)(65)(66). It was proposed that heat responsiveness of some CMH neurons in mice might be indirectly mediated by chemicals released from keratinocytes (60).…”

Puerarin alleviates burn-related procedural pain mediated by P2X3 receptors

“…The P2X 2/3 knockouts display significant reduction in pain reception in response to ATP [9]. Neurons expressing P2X 3 receptors are dramatically more responsive to ATP with even small increases in temperature [13]. P2X 3 expression in sensory neurons was increased after burn injury in the rats [18,54], and P2X 3 receptors are relevant with burn injury pain [18,54].…”

“…P2 purinoceptors responding to ATP are divided into ionotropic receptors (P2X, seven types; P2X 1 -7 ) coupled to ion channels and metabotropic receptors (P2Y, eight types; P2Y 1,2,4,6,11,12,13,14 ) coupled to intracellular secondmessenger systems through heterotrimeric G-proteins [6]. P2 receptors expressed in blood cells regulate responses such as cell proliferation, differentiation, chemotaxis, cytokine release, and immune and inflammatory responses [8,11].…”