Akiko Okada-Ogawa

Astroglia in Medullary Dorsal Horn (Trigeminal Spinal Subnucleus Caudalis) Are Involved in Trigeminal Neuropathic Pain Mechanisms

The aim of this study was to investigate whether astroglia in the medullary dorsal horn (trigeminal spinal subnucleus caudalis; Vc) may be involved in orofacial neuropathic pain following trigeminal nerve injury. The effects of intrathecal administration of the astroglial aconitase inhibitor sodium fluoroacetate (FA) were tested on Vc astroglial hyperactivity [as revealed by glial fibrillary acid protein (GFAP) labeling], nocifensive behavior, Vc extracellular signal-regulated kinase phosphorylation (pERK), and Vc neuronal activity in inferior alveolar nerve-transected (IANX) rats. Compared with sham-control rats, a significant increase occurred in GFAP-positive cells in ipsilateral Vc at postoperative day 7 in IANX rats, which was prevented following FA administration. FA significantly increased the reduced head withdrawal latency to high-intensity heat stimulation of the maxillary whisker pad skin in IANX rats, although it did not significantly affect the reduced escape threshold to low-intensity mechanical stimulation of the whisker skin in IANX rats. FA also significantly reduced the increased number of pERK-like immunoreactive cells in Vc and the enhanced Vc nociceptive neuronal responses following high-intensity skin stimulation that were documented in IANX rats, and glutamine administration restored the enhanced responses. These various findings provide the first documentation that astroglia is involved in the enhanced nociceptive responses of functionally identified Vc nociceptive neurons and in the associated orofacial hyperalgesia following trigeminal nerve injury.

Sustained Morphine-Induced Sensitization and Loss of Diffuse Noxious Inhibitory Controls in Dura-Sensitive Medullary Dorsal Horn Neurons

Overuse of medications used to treat migraine headache can produce a chronic daily headache, termed medication overuse headache (MOH). Although “overuse” of opioids, triptans, and over-the-counter analgesics can all produce MOH, the neuronal mechanisms remain unknown. Headache pain is likely to be produced by stimulation of primary afferent neurons that innervate the intracranial vasculature and the resulting activation of medullary dorsal horn (MDH) neurons. The present study compared the receptive field properties of MDH dura-sensitive neurons in rats treated with morphine to those given vehicle. Animals were implanted with osmotic minipumps or pellets for sustained subcutaneous administration of morphine or vehicle 6–7 d before recording from dura-sensitive neurons. Electrical and mechanical activation thresholds from the dura were significantly lower in chronic morphine-treated animals when compared to vehicle controls. In addition, sustained morphine increased the cutaneous receptive field sizes. The presence of diffuse noxious inhibitory controls (DNICs) was examined by placing the tail in 55°C water during concomitant noxious thermal stimulation of the cutaneous receptive field, usually located in the ophthalmic region. The DNIC stimulus produced significant inhibition of heat-evoked activity in vehicle- but not chronic morphine-treated animals. Inactivation of the rostral ventromedial medulla with 4% lidocaine reinstated DNICs in chronic morphine-treated animals. These results are consistent with studies demonstrating a loss of DNICs in patients that suffer from chronic daily headache and may partially explain why overuse of medication used to treat migraine can induce headaches.

Fractalkine Signaling in Microglia Contributes to Ectopic Orofacial Pain following Trapezius Muscle Inflammation

Fractalkine (FKN) signaling is involved in mechanical allodynia in the facial skin following trapezius muscle inflammation. Complete Freunds adjuvant (CFA) injection into the trapezius muscle produced mechanical allodynia in the ipsilateral facial skin that was not associated with facial skin inflammation and resulted in FKN but not FKN receptor (CX3CR1) expression, and microglial activation was enhanced in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1–C2). Intra-cisterna magna anti-CX3CR1 or anti-interleukin (IL)-1β neutralizing antibody administration decreased the enhanced excitability of Vc and C1–C2 neurons in CFA-injected rats, whereas intra-cisterna magna FKN administration induced microglial activation and mechanical allodynia in the facial skin. IL-1β expression and p38 mitogen-activated protein kinase phosphorylation were enhanced in activated microglia after CFA injection. The excitability of neurons whose receptive fields was located in the facial skin was significantly enhanced in CFA-injected rats, and the number of cells expressing phosphorylated extracellular signal-regulated kinase (pERK) following noxious mechanical stimulation of the facial skin was significantly increased in Vc and C1–C2. We also observed mechanical allodynia of the trapezius muscle as well as microglial activation and increased pERK expression in C2–C6 after noxious stimulation of the trapezius muscle in facial skin-inflamed rats. These findings suggest that FKN expression was enhanced in Vc and C1–C2 or C2–C6 following trapezius muscle or facial skin inflammation, microglia are activated via FKN signaling, IL-1β is released from the activated microglia, and the excitability of neurons in Vc and C1–C2 or C2-C6 is enhanced, resulting in the ectopic mechanical allodynia.

Mechanisms involved in extraterritorial facial pain following cervical spinal nerve injury in rats.

BackgroundThe aim of this study is to clarify the neural mechanisms underlying orofacial pain abnormalities after cervical spinal nerve injury. Nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) expression and astroglial cell activation in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal dorsal horn (C1-C2) neurons were analyzed in rats with upper cervical spinal nerve transection (CNX).ResultsThe head withdrawal threshold to mechanical stimulation of the lateral facial skin and head withdrawal latency to heating of the lateral facial skin were significantly lower and shorter respectively in CNX rats compared to Sham rats. These nocifensive effects were apparent within 1 day after CNX and lasted for more than 21 days. The numbers of pERK-like immunoreactive (LI) cells in superficial laminae of Vc and C1-C2 were significantly larger in CNX rats compared to Sham rats following noxious and non-noxious mechanical or thermal stimulation of the lateral facial skin at day 7 after CNX. Two peaks of pERK-LI cells were observed in Vc and C1-C2 following mechanical and heat stimulation of the lateral face. The number of pERK-LI cells in C1-C2 was intensity-dependent and increased when the mechanical and heat stimulations of the face were increased. The decrements of head withdrawal latency to heat and head withdrawal threshold to mechanical stimulation were reversed during intrathecal (i.t.) administration of MAPK/ERK kinase 1/2 inhibitor PD98059. The area of activated astroglial cells was significantly higher in CNX rats (at day 7 after CNX). The heat and mechanical nocifensive behaviors were significantly depressed and the number of pERK-LI cells in Vc and C1-C2 following noxious and non-noxious mechanical stimulation of the face was also significantly decreased following i.t. administration of the astroglial inhibitor fluoroacetate.ConclusionsThe present findings have demonstrated that mechanical allodynia and thermal hyperalgesia occur in the lateral facial skin after CNX and also suggest that ERK phosphorylation of Vc and C1-C2 neurons and astroglial cell activation are involved in orofacial extraterritorial pain following cervical nerve injury.

Immune and Endocrine Function in Patients With Burning Mouth Syndrome

Objectives:Research suggests that varied etiologic factors are responsible for burning mouth syndrome (BMS). We examined the role of immune and endocrine function in the pathology of BMS. Methods:We conducted a case-control study to evaluate immune (lymphocyte subpopulations) and endocrine (hypothalamus-pituitary-adrenal axis and sympathetic-adrenomedullary system) function in 47 female BMS patients and 47 age-matched female controls presenting at an university clinic. Psychological state was assessed with the Zung Self-Rating Depression Scale and Taylor Manifest Anxiety Scale. Results:BMS patients were significantly more anxious than controls (P=0.011). Plasma adrenaline level was significantly lower (P=0.020) in BMS patients than in controls, and linear regression analysis of all patients combined revealed that depression level was significantly positively associated with plasma noradrenaline and cortisol levels (P=0.002 and 0.001, respectively). However, as compared with controls, BMS patients had a significantly lower CD8(+) cell count (P<0.001) and a significantly higher CD4/CD8 ratio (P=0.002). Discriminant analysis revealed that CD8(+) cell count and CD4/CD8 ratio were independent variables that distinguished BMS patients from controls. Discussion:The immunoendocrine system is substantially involved, and may have a key role, in the mechanism of chronic pain in BMS patients. Immune function was significantly and specifically suppressed in BMS, although the hypothalamic-pituitary-adrenal axis and sympathetic nervous system were predominantly activated by psychological stress that was not specific to BMS.

Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection

In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at different time periods following IANX and resulting in the extraterritorial neuropathic pain in the orofacial region following trigeminal nerve injury.

A Possible Case of Complex Regional Pain Syndrome in the Orofacial Region

OBJECTIVE To present a case of complex regional pain syndrome (CRPS) type II with sympathetic dysfunction and trophic changes in the orofacial region, which was partially responsive to intravenous ketamine. PATIENT The patient was a 68-year-old man who suffered from inveterate pain with trophic changes of the right face and tongue and vasomotor dysfunction on the right side of the face after ipsilateral trigeminal nerve block. Allodynia and hyperalgesia were observed on the affected side of the face. Pain initially improved after sympathetic nerve block, but similar pain returned that was unresponsive to the same procedure. Repeated intravenous administration of low-dose ketamine preceded by intravenous midazolam alleviated the pain, but trophic changes of the tongue persisted. DISCUSSION CRPS in the orofacial region has not been clearly defined and has been infrequently documented. Clinical findings in this patient met the criteria of the International Association for the Study of Pains and Hardens diagnostic criteria for CRPS. The reason for gradual pain relief after induction of intravenous ketamine therapy was unclear, but the fact that only ketamine and not other various pain medicines or procedures alleviated the pain is important to note. CONCLUSION Distinct cases of CRPS involving the orofacial region are rare. Thorough observations and documentation of signs and symptoms may lead to future standardization of diagnostic criteria and treatment strategies for this disorder.

Quantitative evaluation of oral function in acute and recovery phase of idiopathic facial palsy; a preliminary controlled study

Patients with peripheral facial palsy frequently complain of fluid leakage and food retention during meals. We investigated oral function during eating in adults with peripheral facial palsy.

Attenuation of cannabinoid-induced inhibition of medullary dorsal horn neurons by a kappa-opioid receptor antagonist

The kappa-opioid receptor (KOR) antagonist norbinaltorphimine (nor-BNI) attenuates behavioral antinociception produced by spinal administration of the cannabinoid receptor agonist delta-9-tetrahydorcannabinol (THC). The present study examined the ability of nor-BNI to prevent cannabinoid-induced inhibition of medullary dorsal horn (MDH) nociceptive neurons and antinociception produced by the cannabinoid agonist WIN 55,212-2 (WIN-2). Extracellular, single-unit recordings of lamina I and lamina V MDH neurons were performed in urethane anesthetized rats. Heat-evoked activity was measured before and after local brainstem application of nor-BNI or vehicle followed by WIN-2. In both lamina I and lamina V neurons, prior application of nor-BNI prevented the inhibition of heat-evoked activity by WIN-2. In separate experiments, the contribution of KOR to cannabinoid-induced increases in heat-evoked head withdrawal latencies was assessed in lightly urethane-anesthetized rats. Antinociception produced by intrathecal administration of WIN-2 and THC was attenuated by prior administration of nor-BNI. In contrast, antinociception produced by the cannabinoid CP55940 remained unaffected by prior administration of nor-BNI. These results indicate that cannabinoid inhibition of nociceptive reflexes produced by WIN-2 and THC may result from inhibition of dorsal horn neurons through a KOR-dependent mechanism.

Headache attributed to temporomandibular disorders and masticatory myofascial pain

We investigated the temporal association between temporomandibular disorders (TMD)-related symptoms and headache during TMD treatment for patients who fulfilled the diagnostic criteria for headache attributed to TMD (HATMD) specified in the Diagnostic criteria for TMD (DC/TMD) and International classification of headache disorders (ICHD)-3 beta. The study enrolled 34 patients with HATMD induced by masticatory myofascial pain but not by temporomandibular arthralgia. Facial pain intensity, the pressure pain threshold of pericranial muscles, and maximum unassisted opening of the jaw were assessed at an initial examination and before and after physical therapy. The intensity and frequency of headache episodes and tooth contact ratio were also recorded before and after the intervention. Headache intensity and frequency significantly decreased, and these reductions were temporally related to improvements in facial pain intensity, maximum unassisted opening, and pressure pain threshold during TMD treatment. Linear regression analysis showed significant correlations between facial pain intensity and headache intensity and between tooth contact ratio and pressure pain threshold. Among patients who fulfilled the DC/TMD and ICHD-3 beta diagnostic criteria for HATMD, headache improved during TMD treatment, and the improvement was temporally related to amelioration of TMD symptoms. These findings suggest that sensitization in the central and peripheral nervous systems is responsible for HATMD. (J Oral Sci 58, 195-204, 2016).