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Vol. 53, Issue 4, 553-568, December 2001
Department of Pharmacology, Grünenthal GmbH Research Centre,
Aachen, Germany (B.A.C.); and Rudolf-Boehm Institute for Pharmacology
and Toxicology, University of Leipzig, Germany (P.I.)
I. Introduction
II. P2X Receptor Subtypes, Localization, and Pharmacology
A. Subtypes of Ionotropic Receptors for ATP
B. Distribution of P2X Receptors in Pain Relevant Neuronal
Structures
1. Dorsal Root Ganglia and Trigeminal Ganglia.
2. Spinal Cord and Other Central Nervous System Areas.
C. Functional Properties of Different P2X Receptor Subtypes
D. Available P2X Agonist and Antagonist Tools
III. Peripheral P2X Receptors and Nociception
A. Sources of Extracellular ATP in Peripheral Tissues
B. Characteristics of P2X Receptors on Primary Afferents
IV. Central P2X Receptors and Nociceptive Transmission
A. ATP As Nociceptive Neuromodulator or Neurotransmitter
B. P2X Receptor Involvement in Spinal Nociceptive Transmission
V. Role of ATP and P2X Receptors in Different Pain States
A. Acute Pain
B. Inflammatory Pain
C. Neuropathic Pain
D. Visceral Pain
VI. Conclusions
Acknowledgments
References
The potential importance for nociception of P2X receptors, the ionotropic receptors activated by ATP, is underscored by the variety of pain states in which this endogenous ligand can be released. Several important findings have been made recently indicating that P2X receptors can be involved in pain mechanisms both centrally and in the periphery. The roles of ATP at these two sites and the P2X receptor subtypes involved appear to be different. In the periphery, ATP can be released as a result of tissue injury, visceral distension, or sympathetic activation and can excite nociceptive primary afferents by acting at homomeric P2X3 or heteromeric P2X2/3 receptors. Centrally, ATP released from central afferent terminals or second order neurons can modulate neurotransmitter release or postsynaptically activate neurons involved in central nociceptive transmission, with P2X2, P2X4, P2X6, and some other receptors being potentially involved. Evidence from in vivo studies suggests that peripheral ATPergic mechanisms are most important under conditions of acute tissue injury and inflammation whereas the relevance of central mechanisms appears to be more limited. Furthermore, the release of ATP and P2X receptor-mediated afferent activation appear to have been implicated in visceral and neuropathic pain; the importance of the ATPergic component in these states needs to be investigated further. Thus, peripheral P2X receptors, and homomeric P2X3 and/or heteromeric P2X2/3 receptors in particular, constitute attractive targets for analgesic drugs. The development of selective antagonists of these receptors, suitable for a systemic in vivo use although apparently difficult, may prove a useful strategy to generate analgesics with a novel mechanism of action.
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