title: Involvement of glutamate NMDA and AMPA receptors, glial cells and IL-1β in the spinal hyperalgesia evoked by the chemokine CCL2 in mice.
abstract: We study here the involvement of excitatory amino acid receptors, glial cell activation and IL-1β release in the spinal hyperalgesia evoked by the chemokine CCL2 (MCP-1). Three hours after the intrathecal administration of CCL2 (1-100ng), mice exhibit dose-dependent thermal hyperalgesia, that was inhibited by the coadministration of the antagonist of chemokine receptor type 2 (CCR2) RS504393 (0.3-3μg). To assess the involvement of excitatory amino acid receptor sensitisation, CCL2 was coadministered with CPP (0.3-3ng) and NBQX (25-250ng), antagonists of NMDA and AMPA receptors, respectively. Both drugs blocked CCL2-evoked hyperalgesia, strongly suggesting that CCL2 evokes in vivo NMDA and AMPA receptor sensitisation, as previously described in electrophysiological studies. Furthermore, this rapid induction of CCL2-mediated hyperalgesia was blocked by the previous acute administration of the microglial inhibitor minocyclin (4.9μg) or the astroglial inhibitor l-aminoadipate (1.6μg). Since IL-1β can be released by activated glial cells we tested whether this cytokine could be underlying the spinal sensitisation induced by CCL2. The administration of the type I IL-1 receptor antagonist, IL-1ra (3-30μg), partially prevented CCL2-evoked hyperalgesia. Finally, to elucidate if IL-1β could produce NMDA and AMPA receptor sensitisation by itself, we performed experiments in which this cytokine was i.t. administered. Thermal hyperalgesia induced by IL-1β (30pg) was completely prevented by the coadministration of CPP (3ng) but unaffected by NBQX (250ng). Globally, our results suggest that spinal CCL2 induces thermal hyperalgesia by sensitising NMDA and AMPA receptors in a process that involves glial activation and IL-1β release.
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006 Oviedo, Asturias, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000378:metabolism* / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate