The melatonin system dysfunction and the upregulated NMDA receptors in trigeminal nuclei might be involved in trigeminal pain and depression comorbidity.
A connection between pain and depression has long been recognized in the clinical setting; however, its mechanism remains unclear. This study showed that mechanical hyperalgesia induced by unilateral temporomandibular joint (TMJ) inflammation was exacerbated in Wistar-Kyoto (WKY) rats with genetically predisposed depressive behavior. Reciprocally, TMJ inflammation enhanced depressive behavior such that a lower nociceptive threshold correlated with a higher score of depressive behavior in the same WKY rats. As compared with Wistar rats, WKY rats showed a lower plasma melatonin level, downregulation of the melatonin MT1 receptor, but upregulation of the NR1 subunit of the NMDA receptor in the ipsilateral trigeminal subnucleus caudalis (Sp5C). Intracisternal administration of 6-chloromelatonin (250 μg, twice daily for 7 days) concurrently attenuated mechanical hyperalgesia and depressive behavior in WKY rats as well as downregulated the NR1 expression in the ipsilateral Sp5C. In patch-clamp recordings, melatonin dose-dependently decreased NMDA-induced currents in spinal cord dorsal horn substantia gelatinosa neurons. These results demonstrate a reciprocal relationship between TMJ inflammation-induced mechanical hyperalgesia and depressive behavior and suggest that the central melatoninergic system, through modulation of the NMDA receptor expression and activity, may play a role in the mechanisms of the comorbidity between pain and depression.
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aMGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
bDepartment of Physiology, Southern Medical University, Guangzhou, China
cDepartment of Anesthesia, West China Hospital, Sichuan University, Chengdu, Sichuan, China
dCenter for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
*Corresponding author. Address: MGH Center for Translational Pain Research, WACC 324, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA. Tel.: +1 617 726 2338; fax: +1 617 724 2719.
1These authors are contributed equally to this work.
Article history: Received 4 June 2012; Received in revised form 16 August 2012; Accepted 31 August 2012.