• Determining the Neural Correlates of Burning Mouth Syndrome

      Payano Sosa, Janell; Seminowicz, David A.; 0000-0003-1337-3749 (2020)
      In the United States, nearly 1 million people suffer from burning mouth syndrome (BMS), a chronic orofacial pain condition that is largely unrecognized by the medical community and predominantly affects post- and peri-menopausal women. Relatively little in-depth research is available on the condition, and patients often give up seeking treatment. The pain in BMS arises spontaneously (i.e. in the absence of stimuli), but the mechanisms of this spontaneous pain is unclear, and there is limited research on structural and functional brain changes that may occur in a BMS sufferer. The goal of this dissertation was to investigate the central nervous system mechanisms of pain experienced in BMS. We collected: 8-day diaries, morning and afternoon quantitative sensory testing of both orofacial and forearm regions; afternoon structural and functional MRIs, and questionnaires from 27 BMS patients and 33 healthy post-menopausal women. Our hypotheses that, compared to healthy participants BMS patients have: higher pain sensitivity, especially in orofacial regions during the afternoon; lower grey matter volume and higher functional connectivity in nociceptive pathways associated with noxious heat during rest and evoked thermal pain, even after accounting for anxiety, were not supported. Instead, we found a time-of-day-dependent effect during warm detection and cold detection of face and forearm; lower grey matter volume of the dorsolateral prefrontal cortex (DLPFC), and higher grey matter volume of the inferior temporal gyrus and parabrachial nucleus (PBN); lower PBN connectivity with the DLPFC and primary somatosensory cortex (S1); higher connectivity of the right lateral hypothalamus (LH) with posterior insula during warm condition; connectivity of right medial hypothalamus and LH to left DLPFC and right PBN to bilateral S1 not associated with anxiety in BMS compared to healthy participants. Altogether, BMS showed abnormal responses to innocuous stimuli. This was supported by fMRI data, where connectivity differences were mostly present during innocuous stimulation. These altered sensory and brain responses could reflect heightened anticipation of thermal stimuli (both pain-specific and non-pain specific) associated with disruption of communication between regions associated with negative affect of pain (insula), attention modulation of pain (left DLPFC), somatosensation (S1), and thermoregulation (LH and PBN).
    • Sex differences in cannabinoid and opioid mediated analgesia

      Niu, Katelyn Y.; Ro, Jin Y. (2013)
      Orofacial musculoskeletal pain conditions, such as temporomandibular disorder (TMD), are debilitating and often difficult to treat. As with many chronic pain conditions, TMD occurs more frequently in women. Thus, understanding mechanisms underlying sex differences in pain and analgesia is essential for effective pain management in both sexes. This study introduces the potential therapeutic advantage of targeting cannabinoid 1 receptor (CB1) localized in primary afferent neurons under myositis conditions. Although sex differences in CB1 responses are recognized in the CNS, it is not known whether such sex differences exist in the periphery. Therefore, I investigated whether peripheral cannabinoid treatment leads to sex differences in anti-hyperalgesic effects, and whether the effects are mediated by sex differences in CB1 level in trigeminal ganglia (TG) under a rodent orofacial myositis model. Peripherally administered ACPA, a specific CB1 agonist, significantly attenuated inflammation-induced mechanical hypersensitivity in the masseter of male rats. In female rats, a 30-fold higher dose of ACPA was required to produce a reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly up-regulated CB1 mRNA expression in TG from males, but not from females, and CB1 mRNA levels in TG were positively correlated with the anti-hyperalgesic effect of ACPA. IL-1β and IL-6, elevated in the muscle tissue following inflammation, induced a significant up-regulation of CB1 mRNA expression in TG cultures from male rats. The up-regulation of CB1 was prevented in TG cultures from orchidectomized males, and was restored by testosterone treatment. The cytokines did not alter the CB1 mRNA level in TG from intact or ovariectomized female rats. Neither estradiol nor estrogen receptor blockade had any effect on CB1 expression. Similar results were obtained regarding cytokine-induced regulation of μ-opioid receptor (MOR) in TG, another important peripheral target for pain management. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1 and MOR in TG under inflammatory conditions, which explains the sex differences in the anti-hyperalgesic effects of peripherally administered agonists. These data offer important new insights for the development of mechanism-based sex-specific pharmacological treatment alternatives that can be directed at the peripheral anti-nociceptive systems to ameliorate persistent pain.