Phosphorylation of ERK in Trigeminal Spinal Nucleus Neurons Following Passive Jaw Movement in Rats with Chronic Temporomandibular Joint Inflammation

Aims: To elucidate the neuronal mechanisms underlying chronic pain of the temporomandibular joint (TMJ), expression of phosphorylated extracellular signal-regulated kinase (pERK) in the trigeminal spinal nucleus caudalis (Vc) was studied in rats with a chronically inflamed TMJ. Methods: Complete Freund’s adjuvant (CFA) was injected in the left TMJ region of rats anesthetized with pentobarbital (50 mg/kg intraperitoneally). Face temperature of the TMJ region was measured periodically after CFA injection. Two weeks after CFA injection, passive jaw movement with 4-, 6-, and 15-mm distances was carried out in inflamed and naive rats for 5, 15, and 30 minutes. pERK expression was studied in the medulla and upper cervical cord after passive jaw movement. Results: Face temperature was significantly increased 2 days after CFA injection and returned to the preoperative level 7 days later. The pERK-like immunoreactive (LI) cells were observed in the dorsal portion of the rostral Vc in inflamed rats after passive jaw movement, and a small number of pERK-LI cells were observed in naive rats after passive jaw movement. No pERK-LI cells were observed in the TMJ of inflamed rats without jaw movement. The number of pERK-LI cells increased following increases in the jaw-movement distance and duration. Conclusion: These findings suggest that the dorsal portion of the rostral Vc may be involved in mediating chronic pain following TMJ inflammation and that the intracellular ERK cascade may be involved.

chronic inflammation; extracellular signal-regulated kinase; jaw movement; temporomandibular joint; trigeminal spinal nucleus

1. Iwata K, Tashiro A, Tsuboi Y, et al. Medullary dorsal horn neuronal activity in rats with persistent temporomandibular joint and perioral inflammation. J Neurophysiol 1999;82:1244–1253.

2. Bereiter DA, Bereiter DF, Ramos M. Vagotomy prevents morphine-induced reduction in Fos-like immunoreactivity in trigeminal spinal nucleus produced after TMJ injury in a sex-dependent manner. Pain 2002;96:205–213.

3. Bereiter DA, Okamoto K, Bereiter DF. Effect of persistent monoarthritis of the temporomandibular joint region on acute mustard oil-induced excitation of trigeminal subnucleus caudalis neurons in male and female rats. Pain 2005;117:58–67.

4. Dai Y, Iwata K, Fukuoka T, et al. Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. J Neurosci 2002;22:7737–7745.

5. Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 1999;2:1114–1119.

6. Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to c-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci 2004;24:8310–8321.

7. Liu Y, Obata K, Yamanaka H, et al. Activation of extracellular signal-regulated protein kinase in dorsal horn neurons in the rat neuropathic intermittent claudication model. Pain 2004;109:64–72.

8. Shimizu K, Asano M, Kitagawa J, et al. Phosphorylation of extracellular signal-regulated kinase in medullary and upper cervical cord neurons following noxious tooth pulp stimulation. Brain Res 2006;1072:99–109.

9. Zimmerman M. Ethical guidelines for investigation of experimental pain in conscious animals. Pain 1983;16:109–110.

10. Kitagawa J, Kanda K, Sugiura M, et al. Effect of chronic inflammation on dorsal horn nociceptive neurons in aged rats. J Neurophysiol 2005;93:3594–3604.

11. Koyama N, Hirata K, Hori K, et al. Computer-assisted infrared thermographic study of axon reflex induced by intradermal melittin. Pain 2000;84:133–139.

12. Ogawa A, Ren K, Tsuboi Y, Morimoto T, Sato T, Iwata

K. A new model of experimental parotitis in rats and its implication for trigeminal nociception. Exp Brain Res 2003;152:307–316.

13. Zhou Q, Imbe H, Dubner R, Ren K. Persistent Fos protein expression after orofacial deep or cutaneous tissue inflammation in rats: Implications for persistent orofacial pain. J Comp Neurol 1999;412:276–291.

14. Sessle BJ, Greenwood LF. Inputs to trigeminal brain stem neurons from facial, oral, tooth and pharyngolaryngeal tissues. I. Responses to innocuous and noxious stimuli. Brain Res 1976;117:211–226.

15. Hathaway CB, Hu JW, Bereiter DA. Distribution of Foslike immunoreactivity in the caudal brainstem of the rat following noxious chemical stimulation of the temporomandibular joint. J Comp Neurol 1995;356:444–456.

16. Bereiter DA, Cioffi JL, Bereiter DF, et al. Local blockade of integrins in the temporomandibular joint region reduces Fos-positive neurons in trigeminal subnucleus caudalis of female rats produced by jaw movement. Pain 2006;125: 65–73.