P2X3 Receptor Involvement in Pain States

Purinergic pathways are considered important in pain transmission, and P2X receptors are a key part of this system which has received little attention in the horse. The aim of this study was to identify and characterise the distribution of P2X receptor subtypes in the equine digit and associated vasculature and nervous tissue, including peripheral nerves, dorsal root ganglia and cervical spinal cord, using PCR, Western blot analysis and immunohistochemistry. mRNA signal for most of the tested P2X receptor subunits (P2X 1-5, 7 ) was detected in all sampled equine tissues, whereas P2X 6 receptor subunit was predominantly expressed in the dorsal root ganglia and spinal cord. Western blot analysis validated the specificity of P2X [1][2][3]7 antibodies, and these were used in immunohistochemistry studies. P2X 1-3, 7 receptor subunits were found in smooth muscle cells in the palmar digital artery and vein with the exception of the P2X 3 subunit that was present only in the vein. However, endothelial cells in the palmar digital artery and vein were positive only for P2X 2 and P2X 3 receptor subunits. Neurons and nerve fibres in the peripheral and central nervous system were positive for P2X 1-3 receptor subunits, whereas glial cells were positive for P2X 7 and P2X 1 and 2 receptor subunits. This previously unreported distribution of P2X subtypes may suggest important tissue specific roles in physiological and pathological processes.

Section: Discussionmentioning

confidence: 99%

Distribution of purinergic P2X receptors in the equine digit, cervical spinal cord and dorsal root ganglia

Zamboulis

Senior

Clegg

et al. 2013

“…A review includes a discussion of the role of P2X3 receptors in inflammatory pain [102]. During the inflammatory process in peripheral tissue, neither prostaglandins nor sympathetic amines can sensitize primary afferent neurons by themselves; they depend on previous neuronal P2X3 receptor activation [103].…”

Section: Inflammatory Painmentioning

confidence: 99%

P2X ion channel receptors and inflammation

Burnstock

2016

183

153

Neuroinflammation limits tissue damage in response to pathogens or injury and promotes repair. There are two stages of inflammation, initiation and resolution. P2X receptors are gaining attention in relation to immunology and inflammation. The P2X7 receptor in particular appears to be an essential immunomodulatory receptor, although P2X1 and P2X4 receptors also appear to be involved. ATP released from damaged or infected cells causes inflammation by release of inflammatory cytokines via P2X7 receptors and acts as a danger signal by occupying upregulated P2X receptors on immune cells to increase immune responses. The purinergic involvement in inflammation is being explored for the development of novel therapeutic strategies.

“…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]. Recent papers described the rapid transition of the P2X3 receptors to a desensitization state followed by a relatively slow recovery of sensitivity to ATP [13,42].…”

Section: Introductionmentioning

confidence: 99%

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

Ben

Marchenkova

Thomas

et al. 2016

Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABA A and 5-HT 3 receptors, whose membrane currents were unaffected by the tested compounds.