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Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance.
Neuroscience 2007; 147(2):445-55N

Abstract

Several lines of evidence suggest that extracellular ATP plays a role in pain signaling through the activation of ionotropic P2X-receptors, especially homomeric P2X3- and heteromeric P2X2/3-receptors on capsaicin-sensitive and -insensitive primary afferent neurons, respectively, at peripheral and spinal sites. We investigated the mechanisms of the induction and maintenance of mechanical allodynia produced by a single intrathecal (i.t.) administration of ATP in rats. We found that i.t. administration of ATP and the P2X-receptor agonist alpha,beta-methylene-ATP produced tactile allodynia which lasted more than 1 week. The i.t. ATP- and alpha,beta-methylene-ATP-produced long-lasting allodynia remained in neonatal capsaicin-treated adult rats. I.t. administration of a P2X3/P2X2/3-receptor selective antagonist completely prevented the induction (co-administration on day 0) and partially attenuated the early phase (day 1 post-ATP administration), but not the late phase (day 7 post-ATP administration) of maintenance of allodynia. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely prevented the induction phase, but not the early and late phases of maintenance of allodynia. Immunohistochemical and immunoblotting studies for microglial and astrocytic markers revealed that i.t. ATP administration caused spinal microglial activation within 1 day, and astrocytic activation which peaked at 1-3 days after ATP administration. Furthermore, minocycline, a microglial inhibitor, attenuated the induction but not the early and late phases of maintenance, while fluorocitrate, a glial metabolic inhibitor, attenuated the induction and the early phase but not the late phase of maintenance. Taken together, these results suggest that the activation of P2X-receptors, most likely spinal P2X2/3-receptors on capsaicin-insensitive primary afferent neurons, triggers the induction of long-lasting allodynia through NMDA receptors, and the induction and early maintenance phase, but not the late phase, is mediated through the functions of spinal glial cells.

Authors+Show Affiliations

Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. tnakaga@pharm.kyoto-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17543465

Citation

Nakagawa, T, et al. "Intrathecal Administration of ATP Produces Long-lasting Allodynia in Rats: Differential Mechanisms in the Phase of the Induction and Maintenance." Neuroscience, vol. 147, no. 2, 2007, pp. 445-55.
Nakagawa T, Wakamatsu K, Zhang N, et al. Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance. Neuroscience. 2007;147(2):445-55.
Nakagawa, T., Wakamatsu, K., Zhang, N., Maeda, S., Minami, M., Satoh, M., & Kaneko, S. (2007). Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance. Neuroscience, 147(2), pp. 445-55.
Nakagawa T, et al. Intrathecal Administration of ATP Produces Long-lasting Allodynia in Rats: Differential Mechanisms in the Phase of the Induction and Maintenance. Neuroscience. 2007 Jun 29;147(2):445-55. PubMed PMID: 17543465.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance. AU - Nakagawa,T, AU - Wakamatsu,K, AU - Zhang,N, AU - Maeda,S, AU - Minami,M, AU - Satoh,M, AU - Kaneko,S, Y1 - 2007/06/01/ PY - 2006/12/01/received PY - 2007/03/22/revised PY - 2007/03/23/accepted PY - 2007/6/5/pubmed PY - 2007/9/19/medline PY - 2007/6/5/entrez SP - 445 EP - 55 JF - Neuroscience JO - Neuroscience VL - 147 IS - 2 N2 - Several lines of evidence suggest that extracellular ATP plays a role in pain signaling through the activation of ionotropic P2X-receptors, especially homomeric P2X3- and heteromeric P2X2/3-receptors on capsaicin-sensitive and -insensitive primary afferent neurons, respectively, at peripheral and spinal sites. We investigated the mechanisms of the induction and maintenance of mechanical allodynia produced by a single intrathecal (i.t.) administration of ATP in rats. We found that i.t. administration of ATP and the P2X-receptor agonist alpha,beta-methylene-ATP produced tactile allodynia which lasted more than 1 week. The i.t. ATP- and alpha,beta-methylene-ATP-produced long-lasting allodynia remained in neonatal capsaicin-treated adult rats. I.t. administration of a P2X3/P2X2/3-receptor selective antagonist completely prevented the induction (co-administration on day 0) and partially attenuated the early phase (day 1 post-ATP administration), but not the late phase (day 7 post-ATP administration) of maintenance of allodynia. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely prevented the induction phase, but not the early and late phases of maintenance of allodynia. Immunohistochemical and immunoblotting studies for microglial and astrocytic markers revealed that i.t. ATP administration caused spinal microglial activation within 1 day, and astrocytic activation which peaked at 1-3 days after ATP administration. Furthermore, minocycline, a microglial inhibitor, attenuated the induction but not the early and late phases of maintenance, while fluorocitrate, a glial metabolic inhibitor, attenuated the induction and the early phase but not the late phase of maintenance. Taken together, these results suggest that the activation of P2X-receptors, most likely spinal P2X2/3-receptors on capsaicin-insensitive primary afferent neurons, triggers the induction of long-lasting allodynia through NMDA receptors, and the induction and early maintenance phase, but not the late phase, is mediated through the functions of spinal glial cells. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/17543465/Intrathecal_administration_of_ATP_produces_long_lasting_allodynia_in_rats:_differential_mechanisms_in_the_phase_of_the_induction_and_maintenance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(07)00356-9 DB - PRIME DP - Unbound Medicine ER -