TABLE 1

The role of P2X4R in various pain conditions

Pain ConditionSubjects StudiedKey FindingReference
Activity-induced muscle painMale and female C57BL/6 miceImmunohistochemical staining shows P2X4R is upregulated in muscle macrophages, but the data were not split by sex. Intramuscular injection of the P2XR4 blocker 5-BDBD (5-(3-Bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one), or genetic knockdown of P2X4R with a macrophage-specific miRNA, prevented hyperalgesia in both sexes.Oliveira-Fusaro et al., 2020
Peripheral diabetic neuropathyMale Wistar ratsP2X4R protein is upregulated in the dorsal root ganglion, as detected by Western blot. Intrathecal or ganglionar injection of a P2X4R antagonist (PSB-15417), or of intrathecal P2X4R antisense oligodeoxynucleotide, reversed mechanical hypersenstivity.Teixeira et al., 2019
Neuropathic pain (spared nerve injury and chronic constriction injury)Male and female Sprague-Dawley ratsMale rats, but not females, with spared nerve injury had increased P2X4R protein expression in microglia of the dorsal spinal cord. P2X4R antagonist (TNP-ATP) attenuated allodynia in rats with chronic constriction injury but only in males and not females.Mapplebeck et al., 2018
Inflammatory pain (intraplantar injection of complete Freund’s adjuvant)Male and female C57BL/6 miceP2X4R expression was increased in sensory neurons of the dorsal root ganglion in male mice; females were not tested in this experiment. Nevertheless, P2X4R-deficient female mice did not exhibit hypersensitivity to CFA, unlike their wild-type counterparts.Lalisse et al., 2018
Hyperalgesic priming (intraplantar injection of soluble interleukin-6 receptor followed by prostaglandin E2)Male and female Swiss Webster miceIntrathecal injection of TNP-ATP (P2X4R inhibitor) suppressed the initial response to soluble IL-6 receptor in both sexes. Intrathecal TNP-ATP blocked subsequent hyperalgesia to prostaglandin E2 only when given at the time of initial IL-6 receptor administration and only in males. TNP-ATP did not reverse established priming when given after prostaglandin E2 administration.Paige et al., 2018
Partial sciatic nerve ligationMale and female C57BL/6 miceNo sex difference was found in P2rx4 transcript levels in purified peripheral afferent neurons or in isolated microglia after nerve injury.Lopes et al., 2017
Herpetic painFemale C57BL/6 miceP2X4R mRNA level in the spinal dorsal horn and immunoreactivity in spinal microglia were increased. Selective P2X4R antagonist (NP-1815-PX) had an antiallodynic effect when administered intrathecally.Matsumura et al., 2016
Spared nerve injuryMale and female CD1 miceP2rx4 mRNA level is upregulated in dorsal horn spinal cord of male mice but not in females.Sorge et al., 2015
Cancer-induced bone painFemale Sprague-Dawley ratsP2X4R mRNA and protein was upregulated in spinal microglia. Silencing receptor activity with intrathecal P2X4R siRNA attenuated mechanical hypersensitvity.Jin et al., 2014
Inflammatory pain (intraplantar injection of complete Freund’s adjuvant, carageenan, or formalin)Male C57BL/6 miceP2X4R-deficient mice show reduced hypersensitivity and impaired production of PGE2 after intraplantar complete Freund’s adjuvant or carageenan. P2X4R knockout mice also exhibit modest reductions to acute formalin-induced pain but hypersensitivity at baseline on the hotplate assay.Ulmann et al., 2010
Chronic fatigue syndrome comorbid with fibromyalgia syndromeMale and female human subjectsAfter moderate exercise, chronic fatigue syndrome and chronic fatigue syndrome–fibromyalgia syndrome patients showed elevated level of P2RX4 in circulating leukocytes compared with control subjects. Baseline P2RX4 expression did not differ between patients and controls.Light et al., 2009
Inflammatory pain (intraplantar injection of complete Freund’s adjuvant or formalin or intraperitoneal injection of acetic acid) and neuropathic pain (L4 spinal nerve transection)Male C57BL/6 miceP2X4R knockout mice show reduced mechanical, but not cold, allodynia caused by nerve injury. P2X4R knockout also exhibit attenuated inflammatory pain. P2X4R knockout does not affect baseline mechanical or thermal measures, nor does it affect acute models of pain (visceral acetic acid or intraplantar formalin).Tsuda et al., 2009
Inflammatory pain (formalin injection to dorsal paw)Male Lewis ratsP2X4R + immunoreactivity was increased in the spinal cord dorsal horn 7 days after intraplantar formalin injection.Guo et al., 2005
Spinal nerve injuryMale Wistar ratsP2X4R protein was selectively upregulated in spinal cord microglia. Knockdown of P2X4R with P2rx4 antisense oligodeoxynucleotide or P2X4R inhibition with TNP-ATP suppressed mechanical allodynia. Intraspinal injection to naïve rats of ATP-stimulated microglia produced allodynia.Tsuda et al., 2003