• Restorative Dentistry and Endodontics
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• 제19권2호
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• pp.621-632
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• 1994

This experiment was performed to study the effect of capsaicin on the excitatory amino acids (EAAs) neurotransmitter in medullary dorsal horn and to clarify the relationship between substance P and excitatory amino acids. Horizontal slice of rat medullary dorsal horn was prepared and perfused with modified Krebs-Ringer solution in brain slice chamber. Release of EAAs was induced by veratrine and capsaicin were added to perfusion solution to observe the changes in EAA release. Capsaicin and ruthenium red, capsaicin antagonist, were also systemically injected with 50mg/kg in first day and 100mg/kg in second day for 2 days. Medulla oblongata containing the medullary dorsal horn was isolated, homogenized and centrifused. Spernatant was freeze-dried and EAA was determined by HPLC. Release of glutamate and aspartate was significantly increased by veratrine or capsaicin, but veratrine evoked release of EAAs was blocked by capsaicin in vitro, and injected ruthenium red did not have effect on the contents of EMs in vivo. Systemically injected capsaicin evoked the slight decrease in content of glutamate and aspartate in medullary dorsal horn and this effect of capsaicin was unaffected by ruthenium red.

• International Journal of Oral Biology
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• 제37권3호
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• pp.121-129
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• 2012

Previous clinical studies have demonstrated that gabapentin, a drug that binds to the voltage-gated calcium channel ${\alpha}2{\delta}1$ subunit proteins, is effective in the management of neuropathic pain, but there is limited evidence that addresses the participation of glial cells in the antiallodynic effects of this drug. The present study investigated the participation of glial cells in the anti-nociceptive effects of gabapentin in rats with trigeminal neuropathic pain produced by mal-positioned dental implants. Under anesthesia, the left mandibular second molar was extracted and replaced by a miniature dental implant to induce injury to the inferior alveolar nerve. Mal-positioned dental implants significantly decreased the air-puff thresholds both ipsilateral and contralateral to the injury site. Gabapentin was administered intracisternally beginning on postoperative day (POD) 1 or on POD 7 for three days. Early or late treatment with 0.3, 3, or 30 ${\mu}g$ of gabapentin produced significant anti-allodynic effect in the rats with mal-positioned dental implants. On POD 9, in the mal-positioned dental implants group, OX-42, a microglia marker, and GFAP, an astrocyte marker, were found to be up-regulated in the medullary dorsal horn, compared with the naive group. However, the intracisternal administration of gabapentin (30 ${\mu}g$) failed to reduce the number of activated microglia or astrocytes in the medullary dorsal horn. These findings suggest that gabapentin produces significant antinociceptive effects, which are not mediated by the inhibition of glial cell function in the medullary dorsal horn, in a rat model of trigeminal neuropathic pain.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제33권3호
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• pp.227-237
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• 2007

Microglial cell activation is known to contribute to neuropathic pain following spinal sensory nerve injuries. In this study, I investigated its mechanisms in the case of trigeminal sensory nerve injuries by which microglial cell and p38 mitogen-activated protein kinase (p38 MAPK) activation in the medullary dorsal horn (MDH) would contribute to the facial pain hypersensitivity following mandibular nerve transection (MNT). And also investigated the changes of trigeminal ganglion neurons and ERK, p38 MAPK manifestations. Activation of microglial cells was monitored at 1, 3, 7, 14, 28 and 60 day using immunohistochemical analyses. Microglial cell activation was primarily observed in the superficial laminae of the MDH. Microglial cell activation was initiated at postoperative 1 day, maximal at 3 day, maintained until 14 day and gradually reduced and returned to the basal level by 60 days after MNT. Pain hypersensitivity was also initiated and attenuated almost in parallel with microglial cell activation pattern. To investigate the contribution of the microglial cell activation to the pain hypersensitivity, minocycline, an inhibitor of microglial cell activation by means of p38 MAPK inhibition, was administered. Minocycline dose-dependently attenuated the development of the pain hypersensitivity in parallel with inhibition of microglial cell and p38 MAPK activation following MNT. Mandibular nerve transection induced the activation of ERK, but did not p38 MAPK in the trigeminal ganglion. These results suggest that microglial cell activation in the MDH and p38 MAPK activation in the hyperactive microglial cells play an important role in the development of facial neuropathic pain following MNT. The results also suggest that ERK activation in the trigeminal ganglion contributes microglial cell activation and facial neuropathic pain.

• International Journal of Oral Biology
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• 제39권1호
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• pp.49-56
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• 2014

이상의 실험결과들을 요약하면, CFA를 안면영역 피하로 주입하여 발생한 염증성 통증 행위반응은 P2X 수용체의 억제제의 투여로 감소할 수 있었다. 특히 $P2X_7$ 수용체 억제제를 투여하면 진통작용 뿐 아니라 활성화된 신경아교세포 발현을 억제하였다. 이러한 실험 결과는 $P2X_7$ 수용체가 신경아교세포에 영향을 미쳐 안면에서 발생하는 만성 염증성 통증의 발생과 유지에 관여하고 있다는 것을 보여준다. 따라서 중추신경계의 신경아교세포를 조절할 수 있는 중추성 $P2X_7$ 수용체 작용기전은 임상에서 만성 염증성 통증을 보다 효과적으로 치료할 수 있는 새로운 방법을 제시해 줄 수 있다고 생각된다.

• The Korean Journal of Physiology and Pharmacology
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• 제21권4호
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• pp.371-376
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• 2017

The caudal subnucleus of the spinal trigeminal nucleus (medullary dorsal horn; MDH) receives direct inputs from small diameter primary afferent fibers that predominantly transmit nociceptive information in the orofacial region. Recent studies indicate that reactive oxygen species (ROS) is involved in persistent pain, primarily through spinal mechanisms. In this study, we aimed to investigate the role of xanthine/xanthine oxidase (X/XO) system, a known generator of superoxide anion ($O_2{^-}$), on membrane excitability in the rat MDH neurons. For this, we used patch clamp recording and confocal imaging. An application of X/XO ($300{\mu}M/30mU$) induced membrane depolarization and inward currents. When slices were pretreated with ROS scavengers, such as phenyl N-tert-butylnitrone (PBN), superoxide dismutase (SOD), and catalase, X/XO-induced responses decreased. Fluorescence intensity in the DCF-DA and DHE-loaded MDH cells increased on the application of X/XO. An anion channel blocker, 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS), significantly decreased X/XO-induced depolarization. X/XO elicited an inward current associated with a linear current-voltage relationship that reversed near -40 mV. X/XO-induced depolarization reduced in the presence of $La^{3+}$, a nonselective cation channel (NSCC) blocker, and by lowering the external sodium concentration, indicating that membrane depolarization and inward current are induced by influx of $Na^+$ ions. In conclusion, X/XO-induced ROS modulate the membrane excitability of MDH neurons, which was related to the activation of NSCC.

• International Journal of Oral Biology
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• 제40권2호
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• pp.71-77
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• 2015

The activation of glial cells in the spinal cord has been contribute to the initiation and maintenance of pain facilitation induced by peripheral inflammation and nerve injury. The present study investigated effects of botulinum toxin type A (BoNT-A), injected subcutaneously or intracisternally, on the expression of microglia and astrocytes in rats. Complete Freund's Adjuvant (CFA)-induced inflammation was employed as an orofacial chronic inflammatory pain model. A subcutaneous injection of $40{\mu}L$ CFA into the vibrissa pad was performed under 3% isoflurane anesthesia in SD rats. Immunohistochemical analysis for changes in Iba1 (a microglia marker) and GFAP (an astrocyte marker), were performed 5 days after CFA injection. Subcutaneous injection of CFA produced increases in Iba1 and GFAP expression, in the ipsilateral superficial lamia I and II in the medullary dorsal horn of rats. Subcutaneous treatment with BoNT-A attenuated the up-regulation of Iba1 and GFAP expressions induced by CFA injection. Moreover, intracisternal injection of BoNT-A also attenuated the up-regulated Iba1 and GFAP expressions. These results suggest that the anti-nociceptive action of BoNT-A is mediated by modulation activation of glial cells, including microglia and astrocyte.

• International Journal of Oral Biology
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• 제45권3호
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• pp.84-91
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• 2020

The present study investigated the participation of D-serine and NR2 in antinociception produced by blockade of central erythropoietin-producing hepatocellular carcinoma (Eph) A4 (EphA4) signaling in rats with trigeminal neuropathic pain. Trigeminal neuropathic pain was modeled in male Sprague-Dawley rats using mal-positioned dental implants. The left mandibular second molar was extracted under anesthesia, and a miniature dental implant was placed to induce injury to the inferior alveolar nerve. Our current findings showed that nerve injury induced by malpositioned dental implants significantly produced mechanical allodynia; additionally, the inferior alveolar nerve injury increased the expression of D-serine and NR2 subunits in the ipsilateral medullary dorsal horn (trigeminal subnucleus caudalis). Intracisternal administration of EphA4-Fc, an EphA4 inhibitor, inhibited nerve injury-induced mechanical allodynia and upregulated the expression of D-serine and NR2 subunits. Moreover, intracisternal administration of D-amino acids oxidase, a D-serine inhibitor, inhibited trigeminal mechanical allodynia. These results show that D-serine and NR2 subunit pathways participate in central EphA4 signaling after an inferior alveolar nerve injury. Therefore, blockade of D-serine and NR2 subunit pathways in central EphA4 signaling provides a new therapeutic target for the treatment of trigeminal neuropathic pain.

• 대한치과마취과학회지
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• 제10권1호
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• pp.20-26
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• 2010

This type of neuropathic pain(atypical odontalgia) is seen most often in middle-aged women or men after dentoalveolar operation. Atypical odontalgia probably is caused by deafferentation leading to intraneural changes in the medullary dorsal horn. Treatment of this problem is difficult, but some success has been reported in uncontrolled, open-labeled studies using high doses of tricyclic antidepressants. This is the management report of a patient case, that had a neuropathic atypical odontalgia recognized with the right maxillary lateral incisor. The patient was consulted to the Department of Pain Clinics, ENT & Neurology and diagnosed the adenoid cystic carcinoma on left cerebellum and right paranasal sinus with extension to the cavernous sinus. In spite of the osteoplastic craniotomy, neurosurgical mass removal and radiation therapy were done with chemotherapy, atypical odontalgia was continued. In addition to the consultation to Psychology, stress management and antidepressant medication were done and improved slowly.

• The Korean Journal of Physiology and Pharmacology
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• 제19권4호
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• pp.349-355
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• 2015

We examined the effects of peripherally or centrally administered botulinum neurotoxin type A (BoNT-A) on orofacial inflammatory pain to evaluate the antinociceptive effect of BoNT-A and its underlying mechanisms. The experiments were carried out on male Sprague-Dawley rats. Subcutaneous (3 U/kg) or intracisternal (0.3 or 1 U/kg) administration of BoNT-A significantly inhibited the formalin-induced nociceptive response in the second phase. Both subcutaneous (1 or 3 U/kg) and intracisternal (0.3 or 1 U/kg) injection of BoNT-A increased the latency of head withdrawal response in the complete Freund's adjuvant (CFA)-treated rats. Intracisternal administration of N-methyl-D-aspartate (NMDA) evoked nociceptive behavior via the activation of trigeminal neurons, which was attenuated by the subcutaneous or intracisternal injection of BoNT-A. Intracisternal injection of NMDA up-regulated c-Fos expression in the trigeminal neurons of the medullary dorsal horn. Subcutaneous (3 U/kg) or intracisternal (1 U/kg) administration of BoNT-A significantly reduced the number of c-Fos immunoreactive neurons in the NMDA-treated rats. These results suggest that the central antinociceptive effects the peripherally or centrally administered BoNT-A are mediated by transcytosed BoNT-A or direct inhibition of trigeminal neurons. Our data suggest that central targets of BoNT-A might provide a new therapeutic tool for the treatment of orofacial chronic pain conditions.

• 대한소아치과학회지
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• 제28권2호
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• pp.219-227
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• 2001

일차연접부위에서 악안면 영역에서 유래하는 유해자극의 전달 및 처리기전을 이해하고자 horseradish peroxidase를 치수지배 구심성 신경섬유를 표식한 후 연수후각에서 미세구조 및 연접양상을 분석하여 다음과 같은 결과를 얻었다. 표식종말은 소수의 큰 치밀소포가 관찰되는 종말 (S형) 및 다수의 치밀소포를 함유하는 종말 (LDCV형)등 2종류로 분류할 수 있었다. S형 및 LDCV형 표식종말의 연접양식은 유사하였으며, 다수의 표식종말이 1개 혹은 2개의 neurofile과 연접을 이루어 대단히 단순한 연접양상을 보였다. 표식종말은 가지돌기체 보다는 다수의 가지돌기가시와 연접을 이루는 빈도가 높았다. 표식종말이 세포체 및 이에 인접한 근심부 가지돌기와 연접하는 경우는 드물었으며, 소수의 표식종말에서 p-ending과 연접하는 경우를 보였다. 표식종말의 체적, 표면적, 사립체의 체적, neurofile과 접하는 면적, 활성부위의 면적, 단위표식종말당 연접소포의 수 및 연접소포의 밀도등은 넓은 범위의 계측치를 나타내었으며, 이는 S형 및 LDCV형 표식종말 사이에 유의한 차이가 없었다. 이상의 결과로 미루어보아 연수후각에서 치수유래 구심성 신경섬유 종말의 연접양식은 고유의 특징을 보이며, 이는 신경회로의 기능과 밀접한 상관관계를 가지는 것으로 판단되었다.