Nociceptive signaling of P2X receptors in chronic pain states
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REVIEW ARTICLE
Nociceptive signaling of P2X receptors in chronic pain states Kazuhide Inoue 1 Received: 3 September 2020 / Accepted: 27 September 2020 # Springer Nature B.V. 2020
Abstract P2X3 monomeric receptors (P2X3Rs) and P2X2/3 heteromeric receptors (P2X2/3Rs) in primary sensory neurons and microglial P2X4 monomeric receptors (P2X4Rs) in the spinal dorsal horn (SDH) play important roles in neuropathic pain. In particular, P2X4R in the spinal microglia during peripheral nerve injury (PNI), experimental autoimmune neuritis, and herpes models are useful to explore the potential strategies for developing new drugs to treat neuropathic pain. Recently, novel P2X4 antagonists, NP-1815-PX and NC-2600, were developed, which demonstrated potent and specific inhibition against rodent and human P2X4Rs. The phase I study of NC-2600 has been completed, and no serious side effects were reported. The roles played by purinergic receptors in evoking neuropathic pain provide crucial insights into the pathogenesis of neuropathic pain. Keywords Neuropathic pain . P2X3 . P2X2/3 . P2X4 . Primary sensory neurons . Microglia
Introduction Acute nociceptive pain has physiological significance as a warning system under normal conditions. The primary sensory neurons in the dorsal root ganglion (DRG) are pseudo-monopolar cells having one short axonal process that is divided into two directions. One of them is distributed peripherally as a peripheral branch receiving inputs through receptors. The other branch becomes the dorsal root of the spinal cord and transmits impulses from the peripheral receptors to the spinal cord. The primary sensory neurons of DRG are composed of several types of neurons with or without myelin sheaths. Among them, Aδ-fibers, with myelin sheaths, and C-fibers, without sheath, conduct painrelated spikes to spinal dorsal horn (SDH) neurons. Painful stimuli evoke action potentials in the distal ends of the C-fibers or Aδfibers of DRG neurons, and these signals are conducted to the central ends of these DRG neurons and transmitted to the secondary sensory neurons in the SDH. When these signals finally reach the sensory cortex, pain sensation occurs. Evidence suggest that ionotropic P2XRs play important roles in pain signaling under normal conditions [1].
* Kazuhide Inoue [email protected] 1
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Touch stimuli evoke action potentials in the Aβ-fibers of DRG neurons, and these signals are transmitted to the sensory cortex, resulting in touch sensation. These action potentials can also be partially transmitted to the inhibitory interneurons in the SDH, resulting in the release of the inhibitory neurotransmitters, γ-aminobutyric acid (GABA), and glycine. GABA evokes the hyperpolarization of secondary neurons, which inhibits pain signaling. Thus, light touch stimuli do not cause pain sensations but, instead, inhibit pain signaling under normal conditions
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