P2X receptors and acupuncture analgesia.

Purinergic signaling has recently been suggested to constitute the cellular mechanism underlying acupuncture-induced analgesia (AA). By extending the original hypothesis on endogenous opioids being released during AA, Geoffrey Burnstock and Maiken Nedergaard supplied evidence for the involvement of purinoceptors (P2 and P1/A1 receptors) in the beneficial effects of AA. In view of certain pain states (e.g. neuropathic pain) which respond only poorly to therapy with standard analgesics, as well as with respect to the numerous unwanted effects of opioids and non-steroidal anti-inflammatory drugs, it is of great significance to search for alternative therapeutic options. Because clinical studies on AA yielded sometimes heterogeneous results, it is of eminent importance to relay on experiments carried out on laboratory animals, by evaluating the data with stringent statistical methods including comparison with a sufficient number of control groups. In this review, we summarize the state of the art situation with respect to the participation of P2 receptors in AA and try to forecast how the field is likely to move forward in the future.

Enhancement of Muscle T Regulatory Cells and Improvement of Muscular Dystrophic Process in mdx Mice by Blockade of Extracellular ATP/P2X Axis.

Infiltration of immune cells and chronic inflammation substantially affect skeletal and cardiac muscle degeneration in Duchenne muscular dystrophy. In the immune system, extracellular adenosine triphosphate (ATP) released by dying cells is sensed as a danger associated molecular pattern through P2 purinergic receptors. Specifically, the P2X7 subtype has a prominent role in regulating immune system physiology and contributes to inflammasome activation also in muscle cells. Here, we show that in vivo blockade of the extracellular ATP/P2X purinergic signaling pathway by periodate-oxidized ATP delayed the progression of the dystrophic phenotype and dampened the local inflammatory response in mdx mice, a spontaneous mouse model of dystrophin deficiency. Reduced infiltration of leukocytes and macrophages and decreased expression of IL-6 were revealed in the muscles of periodate-oxidized ATP-treated mdx mice. Concomitantly, an increase in Foxp3(+) immunosuppressive regulatory T cells was observed and correlated with enhanced myofiber regeneration. Moreover, we detected reduced concentrations of profibrotic cytokines, including transforming growth factor-ß and connective tissue growth factor, in muscles of periodate-oxidized ATP-treated mdx mice. The improvement of inflammatory features was associated with increased strength and reduced necrosis, thus suggesting that pharmacologic purinergic antagonism altering the adaptive immune component in the muscle infiltrates might represent a promising therapeutic approach in Duchenne muscular dystrophy.

Involvement of ATP in noxious stimulus-evoked release of glutamate in rat medullary dorsal horn: a microdialysis study.

Our electrophysiological studies have shown that both purinergic and glutamatergic receptors are involved in central sensitization of nociceptive neurons in the medullary dorsal horn (MDH). Here we assessed the effects of intrathecal administration of apyrase (a nucleotide degrading enzyme of endogenous adenosine 5-triphosphate [ATP]), a combination of apyrase and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, an adenosine A1 receptor antagonist), or 2,3-O-2,4,6-trinitrophenyl-adenosine triphosphate (TNP-ATP, a P2X1, P2X3, P2X2/3 receptor antagonist) on the release of glutamate in the rat MDH evoked by application of mustard oil (MO) to the molar tooth pulp. In vivo microdialysis was used to dialyse the MDH every 5 min, and included 3 basal samples, 6 samples after drug treatment and 12 samples following application of MO. Tooth pulp application of MO induced a significant increase in glutamate release in the MDH. Superfusion of apyrase or TNP-ATP alone significantly reduced the MO-induced glutamate release in the MDH, as compared to vehicle. Furthermore, the suppressive effects of apyrase on glutamate release were reduced by combining it with DPCPX. This study demonstrates that application of an inflammatory irritant to the tooth pulp induces glutamate release in the rat MDH in vivo that may be reduced by processes involving endogenous ATP and adenosine.

P2X receptors and modulation of pain transmission: focus on effects of drugs and compounds used in traditional Chinese medicine.

Adenosine triphosphate (ATP) is thought to play an important role in nociceptive transmission or pain signals. ATP is implicated in peripheral pain signaling by acting on P2X receptors. ATP can act on cell bodies of primary afferent fibers. Opening of P2X receptor channels and subsequent membrane depolarization are generally regarded as a key element for extracellular ATP to produce pain. Nociceptive neurons express homomeric P2X(3) as well as heteromeric P2X(2/3) receptors. Both types of channels can be expressed separately or together in individual neuron. Selective antagonists for P2X(3) and/or P2X(2/3) receptors may represent a novel series of useful analgesic drugs. In addition to P2X(3) and P2X(2/3) receptors, other subtypes of the P2X receptor family are also involved in the modulation of nocicpetive transmission (e.g. P2X(4), P2X(7) receptors). Chinese traditional medicine, i.e., tetramethylpyrazine (TMP), sodium ferulate (SF) and puerarin can antagonize the nociceptive or pain transmission mediated by P2X(3) and/or P2X(2/3) receptors in primary afferent neurons. P2X(3) and/or P2X(2/3) receptors are the pharmacological targets of TMP, SF and puerarin for the therapeutic treatment of pain. The myocardial ischemic injury enhanced the sensitization of sympathetic afferent neurons with increased intensity of P2X(3), P2X(2/3) immunoreactivity, protein and mRNA expression in SCG, SG or NG neurons. P2X(3), P2X(2/3) receptors antagonist A-317491 inhibited the transmission of cardiac nociceptive response. Myocardial ischemic nociceptive signaling via P2X(3) and P2X(2/3) receptors in the transmission of rat SCG, SG, NG neuronal circuits induces the sympathoexcitatory reflex to exaggerate myocardial tissue injury. Blocking the nociceptive transmission of SCG, SG, NG neuronal circuits mediated by P2X(3) and P2X(2/3) receptors may improve the cardiac dysfunction. P2X(3) and P2X(2/3) receptors in SCG, SG, NG neurons could be considered as new targets for treating myocardial ischemic injury and cardiac arrhythmia.