Browsing School of Dentistry by Subject "secondary hyperalgesia"
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Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Inhibitory SystemStudies have demonstrated analgesic effects of motor cortex (M1) stimulation for several chronic pain disorders such as neuropathic pain and syndromes involving central sensitization. Central sensitization is an important factor in neuropathic pain, clinically manifested as hyperalgesia and allodynia beyond any apparent injury. We predicted M1 transcranial direct current stimulation (tDCS) would mitigate secondary hyperalgesia, with little or no effect on primary hyperalgesia. We used a capsaicin-heat pain (C-HP) model to elicit heat allodynia and secondary mechanical hyperalgesia in pain-free subjects. In an assessor and subject blind randomized sham-controlled trial, we found anodal M tDCS decreased the intensity and area of pinprick hyperalgesia more than cathodal or sham tDCS with a small to moderate effect size. In contrast, we found no difference among treatments on pain ratings during heat allodynia. These findings confirmed our predictions and support the hypothesis that M1-targeted neuromodulation diminishes central sensitization. To elucidate the mechanism driving analgesia, we repeated application of the C-HP model during anodal, cathodal or sham tDCS in an assessor-blind randomized controlled trial while capturing neurophysiological correlates using functional magnetic resonance imaging (fMRI). We hypothesized M1 anodal tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical pain compared to cathodal or sham tDCS. Anodal tDCS normalized effects of central sensitization on mechanical pain responses in the DPM network. Anodal tDCS disrupted the normal covariation of mechanical pain processing with subjective pain intensity and blunted the effect of sensitization in primary somatosensory cortex. There were treatment associated differences in functional connectivity (FC) within the DPM network. We found M1 to PAG FC was significantly greater during pain after anodal versus cathodal tDCS. Differences in FC between pain and control states for anodal tDCS included disrupted FC between PAG and sensory regions in the parietal lobe as well as the rostral ventral medulla. No disruptions in FC between control and pain state were found after cathodal or sham stimulation. These results support the hypothesis that analgesia via M1 neuromodulation occurs through modulation of activity in the DPM network even at the earliest stages of therapy.
Trigeminal-rostral ventromedial medulla involvement in contralateral deep tissue orofacial hyperalgesiaIn 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.