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Abstract
Nitric oxide (NO), a diffusible gas, is produced in the central nervous system, including the spinal cord dorsal horn and the trigeminal nucleus, the first central areas processing nociceptive information from periphery. In the spinal cord, it has been demonstrated that NO acts as pronociceptive or antinociceptive mediators, apparently in a concentration-dependent manner. However, the central role of NO in the trigeminal nucleus remains uncertain in support of processing the orofacial nociception. Thus, we here investigated the central role of NO in formalin (3%)-induced orofacial pain in rats by administering membrane-permeable or -impermeable inhibitors, relating to the NO signaling pathways, into intracisternal space. The intracisternal pretreatments with the NO synthase inhibitor L-NAME, the NO-sensitive guanylate cyclase inhibitor ODQ, and the protein kinase C inhibitor GF109203X, all of which are permeable to the cell membrane, significantly reduced the formalin-induced pain, whereas the membrane-impermeable NO scavenger PTIO significantly enhanced it, compared to vehicle controls. These data suggest that an overall effect of NO production in the trigeminal nucleus is pronociceptive, but NO extracellularly diffused out of its producing neurons would have an antinociceptive action.
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Fig. 1.
Opposite effects of central NOS inhibition and NO scavenging on formalin-induced orofacial pain. Formalin-induced characteristic rubbing behaviors were reduced by intracisternal injection of L-NAME, a NOS inhibitor, in the second phase (10∼60 min), while enhanced by that of PTIO, a scavenger of NO, both in the first (0∼6 min) and the second phases (A). A histogram (B), summarizing the first and the second phases of the formalin-induced pain behaviors observed in rats, demonstrates the significant reduction in the second phase by L-NAME (n=4) and the significant enhancement both in the first and the second phases by PTIO (n=5), compared to saline (n=4). Formalin was injected into the right upper lip at time zero, and the number of rubbing behaviors was counted. ∗∗p<0.01 and ∗p<0.05 vs. saline, #p<0.05 and ##p<0.01 vs. L-NAME.
Fig. 2.
Reduction of formalin-induced orofacial pain by central inhibition of NO-sensitive guanylate cyclase. Formalin-induced characteristic rubbing behaviors were reduced in the second phase by intracisternal injection of ODQ, an inhibitor of NO-sensitive guanylate cyclase (A). GF109203X, a PKC inhibitor, used as a positive effect control, also reduced the second phase of formalin-induced orofacial pain behavior. A histogram (B), summarizing the first and the second phases of the formalin-induced pain behaviors observed in rats, demonstrates the tendency of reduction by ODQ (n=5) and the significant reduction by GF109203X (n=3) in the second phase, compared to that of DMSO negative control (n=3). Formalin was injected into the right upper lip at time zero, and the number of rubbing behaviors was counted. ∗p<0.05 vs. DMSO, #p<0.05 vs. ODQ.
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