Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors

Abstract

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.

Effects of A‐317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

“…Meanwhile, both intrathecal and intraplantar administration of A-317491 were effective against formalin-induced behaviors. Attenuation of similar behaviors has also been found in P2X 3 -deficient animals (Cockayne et al, 2000;Souslova et al, 2000). Taken together, these results demonstrate that both spinal and peripheral P2X 3 receptors contribute to the transmission of nociception following a chemogenic injury.…”

“…ATP is a nonselective agonist with varied potencies for each of the seven ionotropic P2X and eight metabotropic P2Y purinoceptor subtypes currently identified (Ralevic & Burnstock, 1998;Bianchi et al, 1999;Jacobson et al, 2002;Abbracchio et al, 2003). Receptor localization and behavioral studies suggest that more than one of these receptor subtypes is involved in the transmission of peripheral and/or spinal nociceptive signals (Collo et al, 1996;Vulchanova et al, 1996;Cockayne et al, 2000;Souslova et al, 2000;Okada et al, 2002;Yoshida et al, 2002;Tsuda et al, 2003;Wismer et al, 2003).…”

“…Neuronal expression of the P2X 3 receptor is elevated in both the dorsal root ganglion and the ipsilateral spinal cord following chronic constriction injury (CCI) of the sciatic nerve (Novakovic et al, 1999). Furthermore, P2X 3 (À/À) gene-ablated mice show a significant attenuation in spontaneous pain behaviors following administration of ATP or formalin (Cockayne et al, 2000;Souslova et al, 2000), and animals treated with P2X 3 antisense oligonucleotides exhibit reduced thermal hyperalgesia and mechanical allodynia (Barclay et al, 2002;Honore et al, 2002).…”

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

“…receptors (i.e. neuropathic and inflammatory pain, headache pain and migraine) [22,[31][32][33][34][35][36][37][38][39]. As a consequence, targeting these receptors represents an innovative therapeutic strategy to treat both neuropathic and inflammatory pain conditions [40,41].…”

Temperature sensing across species

“…ATP released upon tissue damage produces a sensation of pain, and mice null in P2X 3 lack rapidly desensitizing ATP-gated cation currents. However, an unexpected observation in P2X 3 -null mice is that, in electrophysiological recordings from spinal cord wide dynamic range neurons, they are unable to code the intensity of innocuous warm stimuli but retain sensitivity to noxious heat [98]. Thus, these results suggest that P2X 3 , although it has not been reported to be activated by warm temperatures in vitro, has a role in warm thermosensation in vivo.…”