P2X receptors mediate ATP-induced primary nociceptive neurone activation

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Abstract

ATP-gated P2X ion-channel receptors are localised throughout the mammalian nervous system and have been identified on neurones which participate in conduction of nociceptive information from the periphery to, and within, the CNS. This article briefly reviews recently published research describing the role that ATP and P2X receptors may play in pain perception, highlighting the importance of the P2X3 receptor in this process. The P2X3 receptor subunit is almost exclusively expressed on a subset of small and medium diameter sensory neurones innervating cutaneous and visceral tissue. Activation of P2X receptors present on the peripheral terminals of primary afferents results in neuronal depolarisation and, in conscious animals, leads to the manifestation of acute nociceptive behaviour. Recent animal studies have also shown that P2X3 receptor expression is increased in sensory ganglia following acute neuronal injury, hinting that similar plasticity in the expression of this receptor subtype could underlie the mechanisms involved in a range of conditions characterised by sensory hypersensitivity in man. It is apparent from the evidence available that functional antagonists at specific P2X receptor subtypes could represent an important class of novel analgesic agents.

Introduction

The molecular identification of the ATP-gated P2X3 ion-channel receptor, which is predominantly expressed within small diameter sensory neurones (Chen et al., 1995, Lewis et al., 1995), has rekindled interest in the role that ATP plays as a signalling agent in nociception (Burnstock, 1996, Burnstock and Wood, 1996). This article briefly reviews the evidence that has accumulated in favour of such a role, from the earliest observations hinting at the presence of ATP receptors on peripheral sensory neurones to the most recent data which suggest that P2X receptors participate in the processes underlying some forms of chronic pain.

Even before the identification of distinct ATP receptors there was evidence that ATP could somehow excite primary sensory neurones in human skin to evoke pain sensation. Bleehen and Keele (1977) applied the adenine nucleotides, ATP, ADP and AMP, and adenosine to blister bases and noted that all four agents were algogenic. This observation was supported independently in a study of ATP-evoked vascular changes in human skin by Coutts et al. (1981) who noted that intradermal injection of ATP produced a sensation of persistent burning pain. Both observations hinted strongly that cutaneous nociceptors could somehow respond to ATP as a noxious peripheral stimulus. A receptor-mediated mechanism for this process was confirmed by study of neurones from rat and cat sensory ganglia using patch clamp electrophysiology, showing that ATP gated an inward cationic current resulting in rapid depolarisation of sensory neurones (Krishtal et al., 1983). Subsequent and exhaustive investigation of the molecular biology of ATP-gated cation channels has revealed a family of seven P2X receptors whose distribution in the mammalian nervous system Collo et al., 1996, Humphrey et al., 1998 supports a role for the action of ATP on specific P2X receptor subtypes in nociception, both at the level of the primary afferent neurone and within the CNS.

Section snippets

P2X receptors exist on primary afferent neurones

The presence of functional ionotropic ATP receptors on the cell bodies of dissociated sensory neurones has been recognised for some time and the nature of the evoked cationic currents has been extensively studied (Krishtal et al., 1988, Bean, 1990, Bouvier et al., 1991, Khakh et al., 1995). However, the identification of the P2X3 receptor and its exclusive expression within a subpopulation of small and medium diameter sensory neurones (Chen et al., 1995, Lewis et al., 1995) has provided insight

Functional evidence that P2X receptor activation excites intact primary afferent neurones

The presence of P2X receptors on primary sensory neurones, confirmed by immunocytochemistry and single-cell patch clamp electrophysiology, does not necessarily imply that this receptor subtype can mediate depolarisation of sensory afferents either in intact preparations or in vivo. Moreover, for validation of the hypothesis that ATP can act as an initiator of pain sensation, it must be shown that functional P2X receptors exist on the peripheral terminals of nociceptive neurones. Supportive

Activation of P2X receptors on primary afferent terminals evokes nociception in conscious animals

There is now compelling evidence to suggest that nociception results as a consequence of P2X receptor activation on the peripheral terminals of sensory neurones in conscious animals. Subplantar injection of α,β-methylene ATP, and less potently ATP, results in the dose-related manifestation of behaviours indicative of acute nociception in conscious rats (Bland-Ward and Humphrey, 1997). The nociceptive responses are selectively inhibited by pretreatment with subplantar α,β-methylene ATP,

P2X3 receptor expression is altered during neuronal injury

Two recent studies have highlighted how experimentally-induced peripheral nerve damage results in altered expression of P2X3 receptors on sensory neurones. Following chronic constriction injury (CCI) or axotomy of the rat inferior alveolar nerve, P2X3 receptor expression was increased in the ipsilateral trigeminal ganglion at 4 and 10 days post injury, but had returned to normal levels by day 22 (Eriksson et al., 1998). Similarly, CCI of the rat sciatic nerve led to increased P2X3

Evidence that P2X receptors in the CNS participate in nociceptive transmission

Antidromic stimulation of sensory nerves causes release of ATP from their peripheral terminals, giving rise to speculation that ATP may also be released at the central synapses of sensory neurones during normal afferent trafficking (Holton and Holton, 1954). In situ hybridisation studies have confirmed that mRNA encoding the P2X2, P2X4 and P2X6 receptors are localised in regions of the CNS known to be involved in the processing of noxious input, including lamina II of the spinal dorsal horn,

Summary

Study of ATP receptors in the sensory nervous system has revealed that functional P2X3 and P2X2/3 receptors are present on a specific phenotype of nociceptive neurone, whilst P2X2, P2X4 and P2X6 receptors are localised to structures within the spinal cord and brain involved in conveying noxious information. At the peripheral terminals of sensory afferents, it is likely that ATP released during tissue damage can excite P2X receptors to initiate pain sensation, and that this effect is exaggerated

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