Perspectives in Pharmacology Painful Purinergic Receptors

Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies, including genetic disruption studies and the development of selective antagonists, has indicated that the activation of P2X receptor subtypes, including P2X3, P2X2/3, P2X4 and P2X7, and P2Y (e.g., P2Y2) receptors, can modulate pain. For example, administration of a selective P2X3 antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X4 receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X7 receptor also reduce sensitization in animal models of inflammatory and neuropathic pain, providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Furthermore, activation of P2Y2 receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X3, P2X2/3, and P2Y receptors) or indirectly through neural-glial cell interactions (P2X4 and P2X7 receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity. Pain is a multidimensional sensory process that, acutely, is physiologically adaptive in response to dangerous (e.g., sharp, hot, or chemical stimuli) stimuli in the environment. Persistent pain can range from increased sensitivity to mildly painful stimuli (hyperalgesia) or to otherwise innocuous stimuli (allodynia) (Honore and Jarvis, 2006). It is well appreciated that distinct sensory mechanisms contribute to physiological pain, to pain arising from tissue damage (inflammatory or nociceptive pain), and to pain arising from injury to the nervous system (neuropathic pain). Nociceptive pain is caused by the ongoing activation of Aand C-nociceptors in response to a noxious stimulus. It can be further classified into visceral pain, superficial somatic pain, and deep somatic pain (Honore and Jarvis, 2006; Perl, 2007). Tissue injury results in the release of pronociceptive mediators that sensitize peripheral nerve terminals that can ultimately lead to increased excitability of spinal cord dorsal horn neurons. As such, injury-induced sensitization of peripheral nerves facilitates a sensitization of the central nervous system. A multitude of receptors, transmitters, second messenger systems, transcription factors, and other signaling molecules are now appreciated to be involved in pain pathways (Honore and Jarvis, 2006; Perl, 2007). The ability of ATP (Fig. 1) to modulate neural function has been well documented (Burnstock and Williams, 2000; Burnstock, 2007). Mechanistic understanding of the role for ATP in processing painful sensory information was initially indicated by early demonstrations that ATP was released from sensory nerves (Holton and Holton, 1954; Holton, 1959) and by subsequent data showing that ATP produces fast excitatory action potentials in dorsal root ganglionic (DRG) neurons (Jahr and Jessel, 1983). Whereas the inhibitory effects of adenosine (ADO) and direct acting ADO receptor agonists D.D.-R., S.M., C.-C.S., P.H., and M.F.J. contributed equally to this perspective. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.105890. ABBREVIATIONS: ADO, adenosine; , -meATP, , -methyleneATP; IL-1, interleukin-1; DRG, dorsal root ganglion; TRPV1, transient receptor potential-1; PPADs, pyridoxal phosphate-6-azophenyl-2-4-disulfonic acid; A-317334, S-enantiomer of A-317491. 0022-3565/08/3242-409–415$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 324, No. 2 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 105890/3303143 JPET 324:409–415, 2008 Printed in U.S.A. 409 at A PE T Jornals on M ay 6, 2017 jpet.asjournals.org D ow nladed from