• The involvement of RVM ionotropic glutamate receptors in descending modulation of persistent inflammatory hyperalgesia

      Guan, Yun; Dubner, Ronald (2002)
      Descending pathways from the rostral ventromedial medulla (RVM) modulate spinal nociceptive transmission. Descending pain modulation exhibits dynamic functional changes in response to persistent pain. Glutamate receptors in the RVM are involved in descending pain modulation. However, their roles in descending modulation of persistent inflammatory hyperalgesia are unclear. Behavioral studies showed that intra-RVM microinjection of NMDA produced descending modulation that depended upon the post-inflammatory time period. At 3 hr post-inflammation, NMDA induced facilitation at a lower dose (10 pmol) and an inhibition at a higher dose (1000 pmol). At 24 hr post-inflammation, NMDA (0.1--1000 pmol) produced a dose-dependent inhibition. AMPA (0.1--100 pmol) produced only dose-dependent inhibition at both 3 hr and 24 hr. Importantly, there is a leftward shift in dose-response curves of NMDA- and AMPA-produced modulation at 24 hr post-inflammation, compared to that at 3 hr, suggesting a time-dependent increase in glutamatergic neurotransmission in the RVM after inflammation.;We further identified the molecular mechanisms underlying the enhanced AMPA receptor function. RT-PCR analysis indicated an upregulation of GluR1-flip (5 hr--24 hr), GluR2-flip (24 hr) and GluR2-flop (24 hr) mRNAs in the RVM after inflammation. Western blots demonstrated that GluR1 protein levels were upregulated at 24 hr-3 days post-inflammation. GluR2 protein levels remained unchanged after inflammation. Immunohistochemistry demonstrated an increase in GluR1-like immunoreactivity localized to the RVM at 24 hr post-inflammation. Phosphorylation of GluR1 Ser831 plays an important role in regulation of AMPA receptor function. Western blots indicated a rapid and prolonged increase in phospho-Ser831 GluR1 levels in the RVM after inflammation. The onset of upregulation of GluR1 phosphorylation was blocked by pre-emptive local anesthesia of the injured area and attenuated by pretreatment of NMDA receptor antagonists, PKC and CaMKII inhibitors in the RVM. These findings suggest that AMPA receptors in the RVM undergo selective transcriptional, translational and post-translational modulations following inflammation. These findings support the notion that there is a time-dependent dynamic change in descending modulation after inflammation. This study demonstrates that ionotropic glutamate receptors in the RVM are involved in the descending modulation of inflammatory hyperalgesia and play a role in plasticity in descending pain modulation after persistent pain.
    • Trigeminal-rostral ventromedial medulla involvement in contralateral deep tissue orofacial hyperalgesia

      Chai, Bryan Young; Ren, Ke (2013)
      In 2008, the National Institute of Dental and Craniofacial Research indicated that approximately 10 million Americans suffer from temporomandibular joint disorders (TMJD). Orofacial pain disorders not only impair the quality of life, but also seriously inhibit the health of the patient by impairing a person's ability to eat and drink. Reports have shown that patients with myofascial TMJD experience bilateral thermal hypersensitivity in the trigeminal region (Fernandez-de-las-Penas et al 2010). Our previous studies have shown that complete Freund's adjuvant (CFA)-induced masseter muscle inflammation and microinjection of the pro-inflammatory cytokine interleukin-1&beta (IL-1&beta) into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc) induce contralateral orofacial hyperalgesia in rat models. Furthermore, ventral Vi/Vc second order neurons project to the rostral ventromedial medulla (RVM) (Sugiyo et al 2005), a critical site for descending pain modulation, and substance P (SP) and its neurokinin-1 (NK-1) tachykinin receptor in the RVM are involved in descending pain facilitation (LaGraize et al 2010). We hypothesize that the development of bilateral deep tissue orofacial hyperalgesia after unilateral inflammation involves neuron-glial interactions in the ipsilateral Vi/Vc transition zone, the SP/NK-1 receptor signaling in the RVM, and subsequent activation of RVM 5-HT containing neurons terminating in the contralateral Vi/Vc transition zone. The results showed that 1) microinjection of the IL-1 receptor antagonist into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia, 2) lesions to the ipsilateral Vc did not prevent the development of contralateral hyperalgesia, 3) ibotenic acid lesion of RVM neurons prevented the development of IL-1&beta-induced contralateral hyperalgesia, 4) intra RVM post-treatment injection of the NK-1 receptor antagonists attenuated CFA-induced bilateral hyperalgesia and IL-1&beta-induced bilateral hyperalgesia, 5) serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia, and 6) inhibition of 5-HT3 receptors in the contralateral Vi/Vc attenuated CFA-induced contralateral hyperalgesia. These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms involving the Vi/Vc-RVM circuitry.