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.