Microinjection of IL-1β into the Trigeminal Transition Zone Produces Bilateral NMDA Receptor-Dependent Orofacial Hyperalgesia Involving Descending Circuitry

K. Shimizu#, Bryan Chai#, Stacey C. LaGraize, F. Wei, R. Dubner, K. Ren *
Dept. of NPS, 650 W. Baltimore St.Dental-8 South, Baltimore, MD 21201-1586, USA.

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© 2009 Shimizu et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Dept. of NPS, 650 W. Baltimore St.Dental-8 South, Baltimore, MD 21201-1586, USA; Tel: (410) 706-3250; Fax: (410) 706-0865; E-mail:
# These authors contributed equally to this work.


Our recent studies indicate that the prototypic proinflammatory cytokine IL-1β is upregulated in astroglial cells in the trigeminal interplolaris/caudalis (Vi/Vc) transition zone, a region of the spinal trigeminal complex involved in trigeminal pain processing, after masseter muscle inflammation. Here we investigated the effect of microinjection of IL- 1β into the Vi/Vc transition zone on orofacial nociception. The mechanical sensitivity of the orofacial site was assessed with von Frey microfilaments. The EF50 values, defined as the von Frey filament force (g) that produces a 50% response frequency, were derived and used as a measure of mechanical sensitivity. A significant reduction in EF50 indicates the occurrence of mechanical hyperalgesia/allodynia. Unilateral intra-Vi/Vc IL-1β (0.016-160 fmol) produced hyperalgesia/allodynia dose-dependently, which appeared at bilateral facial sites. The hyperalgesia was detectable as early as 30 min and lasted for 2-6 h (n=6, p<0.01). Intra-Vi/Vc pretreatment with an IL-1receptor antagonist (1 nmol) attenuated the IL-1β-induced hyperalgesia (p<0.01). Pre-injection of AP-5 (10 pmol) and MK-801 (20 pmol), two NMDA receptor antagonists, significantly attenuated IL-1β-induced hyperalgesia (p<0.05). Pretreatment with glial inhibitors fluorocitrate (120 pmol), minocycline (200 pmol) and propentofylline (10 pmol) did not attenuate IL-1β-induced hyperalgesia. Excitotoxic lesions of the rostral ventromedial medulla with ibotenic acid (2 μg) abolished IL-1β-induced contralateral hyperalgesia, suggesting a contribution of descending facilitatory drive. These results suggest that the IL-1β- produced effect on nociception was downstream to glial activation and involves interaction with NMDA receptors.

Keywords: Spinal Trigeminal Complex, Vi/Vc, NMDA Receptor Antagonists, Inflammatory Cytokine, Glial Inhibitors, Rat.