Analgesic Effects of Intrathecal Administration of P2Y Nucleotide Receptor Agonists UTP and UDP in Normal and Neuropathic Pain Model Rats

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Abstract
Recent electrophysiological, behavioral, and biochemical studies revealed that ATP plays a role in facilitating spinal pain transmission via ionotropic P2X nucleotide receptors, although the involvement of metabotropic P2Y nucleotide receptors remains unclear. In the present study, we examined the effects of i.t. administration of P2Y receptor agonists UTP, UDP, and related compounds on nociception in normal rats and tactile allodynia in a neuropathic pain model. In the paw pressure test using normal rats, i.t. administration of UTP (30 and 100 nmol/rat) and UDP (30 and 100 nmol/rat), but not UMP (100 nmol/rat) or uridine (100 nmol/rat), significantly elevated the mechanical nociceptive thresholds, whereas ATP (30 and 100 nmol/rat) and α,β-methylene-ATP (10 and 30 nmol/rat) lowered them. Similarly, in the tail-flick test, UTP (10, 30, and 100 nmol/rat) and UDP (100 nmol/rat) significantly prolonged the thermal nociceptive latency. In the von Frey filament test on normal rats, UTP (100 nmol/rat) and UDP (100 nmol/rat) produced no allodynia to the tactile stimulus, whereas ATP (100 nmol/rat) induced a significant and long-lasting tactile allodynia. In the neuropathic pain model, in which the sciatic nerves of rats were partially ligated, UTP (30 and 100 nmol/rat) and UDP (30 and 100 nmol/rat) produced significant antiallodynic effects. Furthermore, UTP (100 nmol/rat) and UDP (100 nmol/rat) caused no motor deficit in the inclined plane test. Taken together, these results suggest that the activation of UTP-sensitive P2Y2 and/or P2Y4 receptors and the UDP-sensitive P2Y6receptor, in contrast to P2X receptors, produces inhibitory effects on spinal pain transmission.