Purinergic control of neuropathic pain

Understanding the purinergic modulation of neurotransmission has been greatly advanced in recent years by the development of receptor-selective compounds and the ability to manipulate expression of specific receptor subtypes. The use of these tools has resulted in a wealth of evidence demonstrating the importance of adenosine (ADO)-sensitive and adenosine 5'-triphosphate (ATP)-sensitive receptors (P1 and P2, respectively) to the development of pathological nociceptive states, including neuropathic pain. It is likely that more than one of these PI and P2 receptor subtypes is involved in the modulation and/or transmission of pathological nociceptive signals. ATP, acting at sensory neurons in the periphery and spinal cord as well as on glial cells contributes to neural excitability, is pro-nociceptive, and likely participates in the sensitization of the central nervous system during chronic pain. ATP is a nonselective agonist for several ionotropic P2X and metabotropic P2Y receptor subtypes. The homomeric P2X(3), P2X(4), P2X(7), heteromeric P2X(2/3), and possibly P2Y(2), P2Y(4), and P2Y(6) have all been linked to neuropathic pain in preclinical models. In contrast, ADO generally functions as an endogenous inhibitory neuromodulator and produces these effects by activating on a family of G-protein coupled cell surface receptors (A(1), A(2A), A(2B), A(3)). Systemic and intrathecal administration of ADO itself, both preclinically and clinically, reduces neuropathic hypersensitivity, and these effects are likely mediated through activity at the A, receptor subtype. In order to reduce side effects typically related to the administration of ADO, compounds have been identified to allosterically modulate the A, receptor or to limit ADO reuptake. These compounds potently affect neuropathy-related sensitivity with an improved therapeutic window. Thus, advances in the pharmacology of purinergic neurotransmission have led to the development of new strategies to enhance the endogenous actions of ADO and to limit the neuro-excitatory effects of ATP. The contributions of the various purinergic receptors to states of neuropathic pain will be reviewed.