Differential regulation of peripheral IL-1ß-induced mechanical allodynia and thermal hyperalgesia in rats.

This study examined the differential mechanisms of mechanical allodynia and thermal hyperalgesia after injection of interleukin (IL) 1ß into the orofacial area of male Sprague-Dawley rats. The subcutaneous administration of IL-1ß produced both mechanical allodynia and thermal hyperalgesia. Although a pretreatment with iodoresiniferatoxin (IRTX), a transient receptor potential vanilloid 1 (TRPV1) antagonist, did not affect IL-1ß-induced mechanical allodynia, it significantly abolished IL-1ß-induced thermal hyperalgesia. On the other hand, a pretreatment with D-AP5, an N-methyl-d-aspartate (NMDA) receptor antagonist, and NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, blocked IL-1ß-induced mechanical allodynia. Pretreatment with H89, a protein kinase A (PKA) inhibitor, blocked IL-1ß-induced mechanical allodynia but not thermal hyperalgesia. In contrast, pretreatment with chelerythrine, a protein kinase C (PKC) inhibitor, inhibited IL-1ß-induced thermal hyperalgesia. Subcutaneous injections of 2% lidocaine, a local anesthetic agent, blocked IL-1ß-induced thermal hyperalgesia but not IL-1ß-induced mechanical allodynia. In the resiniferatoxin (RTX)-pretreated rats, a subcutaneous injection of IL-1ß did not produce thermal hyperalgesia due to the depletion of TRPV1 in the primary afferent fibers. Double immunofluorescence revealed the colocalization of PKA with neurofilament 200 (NF200) and of PKC with the calcitonin gene-related peptide (CGRP) in the trigeminal ganglion. Furthermore, NMDA receptor 1 (NR1) and TRPV1 predominantly colocalize with PKA and PKC, respectively, in the trigeminal ganglion. These results suggest that IL-1ß-induced mechanical allodynia is mediated by sensitized peripheral NMDA/AMPA receptors through PKA-mediated signaling in the large-diameter primary afferent nerve fibers, whereas IL-1ß-induced thermal hyperalgesia is mediated by sensitized peripheral TRPV1 receptors through PKC-mediated signaling in the small-diameter primary afferent nerve fibers.

Participation of the central p38 and ERK1/2 pathways in IL-1ß-induced sensitization of nociception in rats.

This study examined the participation of central mitogen-activated protein kinases (MAPKs) in the central sensitization produced by a subcutaneous injection of interleukin-1ß (IL-1ß) in male Sprague-Dawley rats. Formalin-induced responses were evaluated 24h after an IL-1ß injection. A subcutaneous injection of 10ng of IL-1ß elevated the formalin-induced scratching response significantly in the second phase compared to the vehicle-treated group. Pretreatment with an IL-1 receptor antagonist reduced the IL-1ß-induced sensitization. Pretreatment with IL-1ß increased the p-ERK and p-p38 expression induced by the formalin injection. Double immunofluorescence data revealed increases in phospho-extracellular signal-regulated kinase (p-ERK) immunoreactive cells that co-localize with neuronal nuclei (NeuN), a neuronal marker, and in phospho-p38 (p-p38) immunoreactive cells that co-localize with NeuN and OX42, a microglia marker. The intracisternal administration of minocycline (50µg), a microglia inhibitor, attenuated the increased formalin-induced scratching responses in the IL-1ß-treated rats. The intracisternal administration of PD98059 (1, 10µg), a MEK inhibitor, and SB203580 (1, 5µg), a p38 inhibitor, also attenuated the number of formalin-induced scratches in the second phase in the IL-1ß-treated rats. These results suggest that the IL-1ß-induced central sensitization of nociception is mediated by the central MAPK pathways, which are activated differentially in the neurons and microglia under inflammatory pain conditions. Therefore, blockade of the MAPK pathways can be as a potential therapeutic target for the central sensitization of inflammatory pain.