• Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Inhibitory System

      Meeker, Timothy Joseph; Greenspan, Joel D. (2017)
      Studies 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.
    • Observational Study Evaluating Pain in Endodontic Patients Diagnosed with Depression – A Pilot Study

      Mannan, Saurabh; Greenspan, Joel D. (2019)
      TITLE: Observational Study Evaluating Pain in Endodontic Patients Diagnosed with Depression – A Pilot Study Saurabh Mannan, Master of Science 2019 Thesis Directed By: Joel Greenspan, PhD AIM: To evaluate the role of depression in endodontic post-procedural pain METHODOLOGY: This prospective observational study enrolled 42 patients that explored the correlation between patient’s level of depression and pain perception following non-surgical root canal treatment (NSRCT). The Hospital Anxiety and Depression Scale (HADS) assessed the patient’s level of anxiety/depression pre-and postoperatively. The patient used a visual analog scale (VAS) to record their pain intensity and feelings of unpleasantness with their dental experience immediately following their NSRCT. Pain diaries recorded pain intensity post-operatively at the 2nd, 4th, and 7th day. A cohort of endodontic patients who were not diagnosed with depression served as controls. RESULT: A total of 41 patients were included, 30 non-depressed patients and 11 patients diagnosed with depression by their physicians. Two patients did not return the pain dairy. Therefore, data from 29 non-depressed patients and ten depressed patients were available for analysis. This study showed that the diagnosis of depression was significantly associated with both higher immediate post-operative pain and immediate sensations of unpleasantness. Furthermore, HADS ≥ 8 was found to be a significant predictor of greater post-operative pain at day two. CONCLUSIONS: Within the limitations of this study, either a diagnosis of depression or signs of anxiety or depression are a positive predictor of greater post-operative pain.
    • A Phase 3, Multi-Center, Randomized, Double-Blind, Parallel-Groups Clinical Trial Comparing the Efficacy and Safety of Intranasally Administered Kovacaine Mist to Placebo for Anesthetizing Maxillary Teeth in Adults

      Sabti, Mohammad Y.; Gordon, Sharon M. (2014)
      Problem: Fear of a painful dental injection and subsequent avoidance behavior are significant barriers to regular visits to the dentist. An anesthetic procedure that would avoid the discomfort of a local anesthetic injection thus obviating fear and anxiety about receiving a "shot," would greatly benefit dental patients. Methods: The study employed a multi-center, randomized, double-blind, placebo-controlled, parallel-groups design to assess the safety and efficacy of Kovacaine Mist delivered intranasally for inducing pulpal anesthesia of maxillary teeth sufficient to allow completion of the Study Dental Procedure. A total of 36 subjects, randomized 2:1 (Kovacaine Mist: Placebo) were enrolled. Results: Kovacaine Mist was significantly superior to placebo (p<0.0001) with respect to the proportion of subjects who did not require rescue by injection of local anesthetic to complete the Study Dental Procedure. Conclusions: Based of the results of this clinical trial, a nasal anesthetic, such as kovacaine mist, could potentially be used as a safe and effective alternative to maxillary infiltration for anesthetizing maxillary premolars and anteriors to achieve pulpal anesthesia.
    • Switch of GABAA signaling with persistent inflammation

      Zhu, Yi; Gold, Michael S., Ph.D. (2012)
      Following inflammation there is a switch in spinal GABAA signaling from inhibition to excitation such that GABA receptors contribute to inflammatory hyperalgesia. We hypothesized that this switch occurs in primary afferent neurons, as a result of a steady state and/or dynamic depolarizing shift in the reversal potential of GABAA currents (EGABA) which is coupled to an increase in high affinity extrasynaptic GABAA receptors. To test this hypothesis, back labeled, acutely dissociated cutaneous dorsal root ganglion (DRG) neurons from naïve and inflamed rats were studied with a variety of techniques including Ca2+ imaging and patch-clamp electrophysiology. With calcium imaging, GABAA receptor activation was shown to be inhibitory in neurons from naïve animal but was facilitatory or directly exciting in neurons from inflamed rats. Results from gramidicin perforated patch showed that a steady-state depolarizing shift in EGABA was not responsible for this shift in signaling. Rather, the shift appeared to be due to a combination of changes including an increase in GABAA current, a decrease in K+ current, and a depolarizing shift in resting membrane potential. The increase in GABAA current was associated with an increase in both high and low affinity currents which was due to a persistent increase in the relative activity of tyrosine kinase, resulting in part to a decrease in receptor internalization, rather than a change in subunit expression or protein. Dynamic regulation of EGABA was also observed in association with neural activity, but the shift in EGABA was hyperpolarizing, and likely to be due to the activation of a Cl- channel rather than a change in secondary ion transporter activity. Interestingly, inflammation was associated with a decrease in the activity dependent shift in EGABA. Our results indicate that the inflammation-induced switch in GABAA signaling is a complex process that involves the modulation of multiple channels and Cl- equilibrium potential and suggested different approaches to prevent the hyperalgesic effect of GABA.
    • The Contribution of TRPV1 S801 Phosphorylation to Nociception and Inflammatory Pain in Vivo

      Joseph, John; Chung, Man-Kyo (2020)
      Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation permeable channel activated by painful stimuli, such as capsaicin and noxious heat, and enriched in many primary afferent neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, which results in nociceptor sensitization. And this can result in a lower threshold for pain. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in wildtype (WT) controls. In sensory neurons from KI mice, following the activation of PKC, the usual increase of capsaicin-induced currents was substantially impaired. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Thermal hyperalgesia was only marginally attenuated in KI mice duirng inflammation. In contrast, PMA-evoked nocifensive responses and hyperalgesia to capsaicin were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and the pain was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo. Further, this suggests that interference with TRPV1 S801 phosphorylation might represent a potential way to reduce inflammatory pain in the clinic, yet spare basal sensitivity and produce fewer side effects than with a more general TRPV1 inhibition.
    • The Role of Nociceptors in Orthodontic Tooth Movement, Pain, and Alveolar Bone Remodeling

      Elnabawi, Omar; Pae, Eung-Kwon (2018)
      Objective: To determine the effects of selectively ablating transient receptor potential vanilloid 1 (TRPV1)-expressing nociceptors on orthodontic tooth movement, pain, and alveolar bone remodeling. Methods: Resiniferatoxin (RTX) or vehicle was stereotaxically injected into left trigeminal ganglia in adult C57BL/6 mice. After 1 week, orthodontic spring was placed between left maxillary first molar and upper incisors. Pain level was evaluated by measuring mouse grimace scale (MGS) and bite force before and after 1, 3, and 7 days following the procedures. After 12 days, micro-CT was used to quantify tooth movement and analyzing alveolar bone changes. Results: Experimental tooth movement increased MGS scores and decreased bite force. RTX ablation of TRPV1+ nociceptors attenuated MGS scores and relieved the reduction in bite force. The extent of tooth movement was decreased in RTX-treated group, but interradicular alveolar bone volume was not affected. Conclusion: Selective ablation of TRPV1+ nociceptors significantly decreases tooth movement and 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.