Antagonist of transient receptor potential melastatin 2 suppresses mechanical hypersensitivity and activation of microglia induced by infraorbital nerve ligation in male rats.

Activation of microglia is known to be involved in neuropathic pain. However, the pathway that regulates the microglial activation is not completely understood. Transient receptor potential (TRP) melastatin 2 (TRPM2), which is part of the TRP superfamily, is reportedly expressed on microglia and is suggested to be involved in neuropathic pain. To explore the effect of a TRPM2 antagonist on orofacial neuropathic pain and the relationship between TRPM2 and the activation of microglia, experiments were conducted using male rats that underwent infraorbital nerve (ION) ligation as orofacial neuropathic pain models. TRPM2 expression was detected on microglia in the trigeminal spinal subnucleus caudalis (Vc). The immunoreactivity of TRPM2 in the Vc increased after ION ligation. Mechanical threshold for head-withdrawal response was measured using von Frey filament, and it decreased after ION ligation. When the TRPM2 antagonist was administered to the ION-ligated rats, the low mechanical threshold for head-withdrawal response increased, and the number of phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells in the Vc decreased. The number of CD68-immunoreactive cells in the Vc also decreased after the administration of the TRPM2 antagonist in the ION-ligated rats. These findings suggest that TRPM2 antagonist administration suppresses hypersensitivity to mechanical stimulation induced by ION ligation and microglial activation, and TRPM2 is also involved in microglial activation in orofacial neuropathic pain.

Cerebroventricular administration of anti-calcitonin gene-related peptide antibody reduces the increase of dopamine D2 receptor observed in the trigeminal spinal subnucleus caudalis following infraorbital nerve ligation.

A dopamine D2 receptor (D2R) agonist and an anti-calcitonin gene-related peptide (CGRP) antibody were separately reported to reduce neuropathic pain. To further attenuate neuropathic pain, co-administration of a D2R agonist and an anti-CGRP antibody was performed in a rat with the infraorbital nerve (ION) ligation. However, this co-administration showed no further attenuation of mechanical hypersensitivity compared to the administration of anti-CGRP antibody alone. Our results also revealed that D2R immunoreactivity in the trigeminal spinal subnucleus caudalis (Vc) increased following the nerve ligation and decreased following administration of an anti-CGRP antibody. The ratio of immunoreactive neurons of phosphorylated cyclic adenosine monophosphate-response-element-binding protein in the Vc also increased following nerve ligation and decreased with the anti-CGRP antibody. Our results suggest that a decrease in D2R immunoreactivity reduces the effect of a D2R agonist, and transcription of D2R is activated following the ION ligation and suppressed by treatment with an anti-CGRP antibody.

Anti-calcitonin gene-related peptide antibody attenuates orofacial mechanical and heat hypersensitivities induced by infraorbital nerve injury.

Currently, limited information regarding the role of calcitonin gene-related peptide (CGRP) in neuropathic pain is available. Intracerebroventricular administrations of an anti-CGRP antibody were performed in rats with infraorbital nerve ligation. Anti-CGRP antibody administration attenuated mechanical and heat hypersensitivities induced by nerve ligation and decreased the phosphorylated extracellular signal-regulated kinase expression levels in the trigeminal spinal subnucleus caudalis (Vc) following mechanical or heat stimulation. An increased CGRP immunoreactivity in the Vc appeared after nerve ligation. A decreased CGRP immunoreactivity resulted from anti-CGRP antibody administration. Our findings suggest that anti-CGRP antibody administration attenuates the symptoms of trigeminal neuropathic pain by acting on CGRP in the Vc.

Dopaminergic Modulation of Orofacial Mechanical Hypersensitivity Induced by Infraorbital Nerve Injury.

While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABAA) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain.

Changes in the analgesic mechanism of oxytocin can contribute to hyperalgesia in Parkinson's disease model rats.

Pain is a major non-motor symptom of Parkinson's disease (PD). Alterations in the descending pain inhibitory system (DPIS) have been reported to trigger hyperalgesia in PD patients. However, the underlying mechanisms remain unclear. In the current study, dopaminergic nigrostriatal lesions were induced in rats by injecting 6-hydroxydopamine (6-OHDA) into their medial forebrain bundle. The neural mechanisms underlying changes in nociception in the orofacial region of 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad. The 6-OHDA-lesioned rats were seen to exhibit increased frequency of face-rubbing and more c-Fos immunoreactive (c-Fos-IR) cells in the trigeminal spinal subnucleus caudalis (Vc), confirming hyperalgesia. Examination of the number of c-Fos-IR cells in the DPIS nuclei [including the midbrain ventrolateral periaqueductal gray, the locus coeruleus, the nucleus raphe magnus, and paraventricular nucleus (PVN)] showed that 6-OHDA-lesioned rats exhibited a significantly lower number of c-Fos-IR cells in the magnocellular division of the PVN (mPVN) after formalin injection compared to sham-operated rats. Moreover, the 6-OHDA-lesioned rats also exhibited significantly lower plasma oxytocin (OT) concentration and percentage of oxytocin-immunoreactive (OT-IR) neurons expressing c-Fos protein in the mPVN and dorsal parvocellular division of the PVN (dpPVN), which secrete the analgesic hormone OT upon activation by nociceptive stimuli, when compared to the sham-operated rats. The effect of OT on hyperalgesia in 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad after intracisternal administration of OT, and the findings showed a decrease in the frequency of face rubbing and the number of c-Fos-IR cells in the Vc. In conclusion, these findings confirm presence of hyperalgesia in PD rats, potentially due to suppression of the analgesic effects of OT originating from the PVN.

Effects of hippocampal damage on pain perception in a rat model of Alzheimer's disease induced by amyloid-ß and ibotenic acid injection into the hippocampus.

Patients with Alzheimer's disease (AD) present with a variety of symptoms, including core symptoms as well as behavioral and psychological symptoms. Somatosensory neural systems are generally believed to be relatively unaffected by AD until late in the course of the disease; however, somatosensory perception in patients with AD is not yet well understood. One factor that may complicate the assessment of somatosensory perception in humans centers on individual variations in pathological and psychological backgrounds. It is therefore necessary to evaluate somatosensory perception using animal models with uniform status. In the current study, we focused on the hippocampus, the primary site of AD. We first constructed a rat model of AD model using bilateral hippocampal injections of amyloid-ß peptide 1-40 and ibotenic acid; sham rats received saline injections. The Morris water maze test was used to evaluate memory impairment, and the formalin test (1 % or 4 % formalin) and upper lip von Frey test were performed to compare pain perception between AD model and sham rats. Finally, histological and immunohistochemical methods were used to evaluate tissue damage and neuronal activity, respectively, in the hippocampus. AD model rats showed bilateral hippocampal damage and had memory impairment in the Morris water maze test. Furthermore, AD model rats exhibited significantly less pain-related behavior in phase 2 (the last 50 min of the 60-minute observation) of the 4 % formalin test compared with the sham rats. However, no significant changes were observed in the von Frey test. Immunohistochemical observations of the trigeminal spinal subnucleus caudalis after 4 % formalin injection revealed significantly fewer c-Fos-immunoreactive cells in AD model rats than in sham rats, reflecting reduced neuronal activity. These results indicate that AD model rats with hippocampal damage have reduced responsiveness to persistent inflammatory chemical stimuli to the orofacial region.

A Case of Wide QRS Tachycardia After the Local Administration of Epinephrine to Reduce Bleeding During General Anesthesia.

We report a case of wide QRS tachycardia or ventricular tachycardia with a pulse after the administration of epinephrine under general anesthesia. After induction and achieving a sufficiently deep plane of general anesthesia, gauze soaked in a 1:100,000 epinephrine solution was applied to the patient's nasal mucosa and 1% lidocaine with 1:100,000 epinephrine was administered via intraoral infiltration. Several minutes after the start of surgery, the patient's blood pressure and heart rate suddenly increased and a wide QRS tachycardia was observed on the electrocardiogram, which then reverted to a normal sinus rhythm. According to the past reports, similar arrhythmias have occurred after administration of epinephrine in the head and neck. These findings suggest that anesthesia providers must be aware of the risks associated with epinephrine and local anesthetic use, particularly in the head and neck region.

Clinical Use of Preformed Microcuff® Pediatric Endotracheal Tubes in Japan.

Preformed cuffed oral endotracheal tubes are widely used to intubate children undergoing oral surgery. To evaluate the efficacy and safety of oral Ring-Adair-Elwyn (RAE) Microcuff® pediatric endotracheal tubes, we retrospectively investigated the endotracheal tube exchange rate and associated complications in Japanese children younger than 2 years of age undergoing cheiloplasty or palatoplasty. The exchange rate was 3.5%, and although unplanned extubations occurred in 2 patients, no severe complications were observed. Our results suggest that oral RAE Microcuff® tubes are effective and safe for intubating Japanese children younger than 2 years of age, with a low tube exchange rate and minor complications.