Acute inflammation reveals GABAA receptor‐mediated nociception in mouse dorsal root ganglion neurons via PGE ₂ receptor 4 signaling

Jang, In Jeong,Davies, Alexander J.,Akimoto, Nozomi,Back, Seung Keun,Lee, Pa Reum,Na, Heung Sik,Furue, Hidemasa,Jung, Sung Jun,Kim, Yong Ho,Oh, Seog Bae John Wiley and Sons Inc. 2017 Physiological reports Vol.5 No.8

<P><B>Abstract</B></P><P>Gamma‐aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl<SUP>−</SUP> permeable GABAA receptors but the physiologic role of GABAA receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABAA receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABAA receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre‐conditioning with formalin but had no effect in saline‐treated mice. GABAA receptor‐mediated pain behavior after acute formalin treatment was abolished by the GABAA receptor blocker picrotoxin and cyclooxygenase inhibitor indomethacin. In addition, treatment with prostaglandin E2 (PGE<SUB>2</SUB>) was sufficient to reveal muscimol‐induced licking behavior. In vitro, GABA induced sub‐threshold depolarization in DRG neurons through GABAA receptor activation. Both formalin and PGE<SUB>2</SUB> potentiated GABA‐induced Ca<SUP>2+</SUP> transients and membrane depolarization in capsaicin‐sensitive nociceptive DRG neurons; these effects were blocked by the prostaglandin E2 receptor 4 (EP4) antagonist AH23848 (10 <I>μ</I>mol/L). Furthermore, potentiation of GABA responses by PGE<SUB>2</SUB> was prevented by the selective Na<SUB>v</SUB>1.8 antagonist A887826 (100 nmol/L). Although the function of the Na<SUP>+</SUP>‐K<SUP>+</SUP>‐2Cl<SUP>‐</SUP> co‐transporter NKCC1 was required to maintain the Cl<SUP>‐</SUP> ion gradient in isolated DRG neurons, NKCC1 was not required for GABAA receptor‐mediated nociceptive behavior after acute inflammation. Taken together, these results demonstrate that GABAA receptors may contribute to the excitation of peripheral sensory neurons in inflammation through a combined effect involving PGE<SUB>2</SUB>‐EP4 signaling and Na<SUP>+</SUP> channel sensitization.</P>

Glyoxal-induced exacerbation of pruritus and dermatitis is associated with <i>staphylococcus aureus</i> colonization in the skin of a rat model of atopic dermatitis

Han, Rafael Taeho,Kim, Hye Young,Ryu, Hyun,Jang, Wooyoung,Cha, Seung Ha,Kim, Hyo Young,Lee, JaeHee,Back, Seung Keun,Kim, Hee Jin,Na, Heung Sik Elsevier 2018 Journal of dermatological science Vol.90 No.3

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease associated with hyperreactivity to environmental triggers. Among those, outdoor air pollutants such as particulate matter (PM) have been reported to aggravate pre-existing AD. However, underlying mechanisms of air pollution-induced aggravation of AD have hardly been studied.</P> <P><B>Objective</B></P> <P>To investigate the molecular mechanisms by which glyoxal, a PM-forming organic compound, exacerbates the symptoms of AD induced by neonatal capsaicin treatment.</P> <P><B>Methods</B></P> <P>Naïve and AD rats had been exposed to either fresh air or vaporized glyoxal for 5 weeks (2 h/day and 5 days/week) since one week of age. Pruritus and dermatitis were measured every week. The skin and blood were collected and immunological traits such as Staphylococcus aureus skin colonization, production of antimicrobial peptides and immunoglobulin, and mRNA expression of inflammatory cytokines were analyzed.</P> <P><B>Results</B></P> <P>Exposure to glyoxal aggravated pruritus and dermatitis in AD rats, but did not induce any symptoms in naïve rats. Staphylococcus aureus skin colonization was increased in the skin of both naïve and AD rats. Expression of antimicrobial peptides such as LL-37 and β-defensin-2 was also increased by exposure to glyoxal in the skin of both naïve and AD rats. The mRNA expression of Th1-related cytokines was elevated on exposure to glyoxal. However, serum immunoglobulin production was not significantly changed by exposure to glyoxal.</P> <P><B>Conclusion</B></P> <P>In AD rats, exposure to glyoxal exacerbated pruritus and cutaneous inflammation, which was associated with increased colonization of <I>S. aureus</I> and subsequent immunological alterations in the skin.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Exposure to glyoxal aggravated the symptoms in AD rats, but did not induce AD in naïve rats. </LI> <LI> <I>S. aureus</I> skin colonization and subsequent expression of antimicrobial peptides were increased after exposure to glyoxal. </LI> <LI> Exposure to glyoxal elevated the production of Th1-related cytokines such as TNF-α and IFN-γ in the AD lesional skin. </LI> </UL> </P>

Three-Dimensional Z-Plasty(Yoon's Method)를 이용한 내안각 췌피 성형술

박흥식,김우신,윤진호,나민화,김한중 대한미용성형외과학회 1997 Archives of Aesthetic Plastic Surgery Vol.3 No.1

The presence of epicanthal folds in Asian eyelids is one of their unique features, in combination with the lack of supratarsal folds. Western culture has influenced many people to prefer to eliminate the prominent epicanthal fold. A number of surgical techniques have been suggested for their correction. However, difficulty with design, excessive and prominent scarring of medial canthal and nasal area, recurrence, and rigidity of application are potential problems associated with many procedures. This paper describes a epicanthoplasty with three-dimensional Z-plasty. Through epicanthal fold incision, the medial canthal tendon is medially advanced and sutured to the periosteum of nasal bone. After the transposition of the flaps, trimming of the flap is usually required. Three-dimensional Z-plasty creates the attractive eyes. From March, 1995 to March, 1997, the technique was applied to 37 patients with epicanthal fold and was performed with or without double-fold operation. There were 34 females and 3 males with ages ranging from 17 to 30 years. Through 2 years follow-up, this technique has delivered esthetically good results with minimal postoperative scar and could made the reduction of ICD from 40 ± 2.13 mm to 34 ± 1.98 mm. The advantages of epicanthoplasty procedure using three-dimensional Z-plasty(Yoon's method) are as follows; 1) simple in design 2)minimal postoperative scar in the medial canthal area 3) versatile in its application 4) no recurrence 5) no hypertrophic scar 6) preserving ethnic identity.

재관류하는 혈액의 조성 변화에 따른 부정맥의 양상

박금수,나흥식,남숙현 고려대학교 의과대학 1991 고려대 의대 잡지 Vol.28 No.1

To determine the cause of genesis of reperfusion arrhythmias, the left anterior descending coronary artery was cannulated and perfused by a carotid-coronary bypass wlth slde branch in 29 open-chest pentobarbital-anesthetized cats . Ischemia was produced by shunt occlusion during 20min. Thereafter the side branch was opened and the ischemic myocardium reperfused with unmodified arterial blood (13 cats). acidlc blood(pH 6.73-7.10, 8 cats), hypocalcemic blood(Ca^(++) 0.13-0.37mM, 3 cats), and venous blood(PO_2, 29.5-47.ImmHg, 3 cats). Each group was evaluated with respect to the incidence of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation and the onset time of first arrhythmia of each arrhythmia in cats. The incidence of ventricular tachycardia was much lower in the acidic reperfusion group (three of 8 cats,38%) than in the unmodilfed reperfusion group(eleven of 13 cats. 85%), (p<0.O5) hypocalcemic reperfuslon group(three of 3 cats. 100%), and hypoxic reperfusion group(three of 3 cats, 100% ). And the incidence of ventricular fibrillation was much lower in the acidic reperfusion group(none of 8 cats, 0%) than in the unmodified reperfusion group(eleven of 13 cats, 85%),(p<0.O5) hypocalcemic reperfusion group(three of 3 cats, 100%), and hypoxic reperfusion group(two of 3 cats, 67%). The onset time of ventricular premature beat and ventricular tachycardia is later in acidic reperfusion group(158.9 ± 117.5sec., 70.8±54.70sec. (mean±S.E) than unmodified reperfusion group(6.78±1.29sec., 24.7±7.5sec. (mean±S.E.)). These results indicate that acidic reperfusion can prevent reperfusion-induced arrhythmias, presumably owing to a reduction of Ca^(++) influx into cells through Na^(++) -Ca^(++) exchange.

Capsaicin이 성숙한 흰쥐의 통각반응과 open-field 행동에 미치는 영향

박순권,김현택,나흥식,홍승길 한국심리학회 한국심리학회지 생물 및 생리 Vol.7 No.1

성숙한 흰쥐에게 전신계로 투여한 capsaicin(150㎎/㎏)이 개방장(open-field)행동과 통각반응의 역치 및 반응잠재기에 미치는 효과를 알아보았다. 첫째, open-field행동에는 capsaicin의 효과가 관찰되지 않았는데 이것은 capsaicin이 흰쥐의 정서반응성과 운동기능에는 영향을 미치지 않음을 의미하는 것이다. 둘째, capsaicin 투여에 의해 열자극에 대한 앞발 및 뒷발핥기의 역치는 변화되지 않았으나, 뛰어오르기의 역치는 증가되었다. 또한 역치 이상의 열자극에 대한 뒷발핥기 반응의 잠재기도 capsaicin 투여에 의해 증가되었다. 이 결과는 비교적 약한 열자극에 대한 적응반응에는 capsaicin이 영향을 미치지 않으나 강한 열자극에 대한 대처반응에는 영향을 미치는 것으로 해석된다. We investigated the effects of capsaicin(s.c. 150㎎/㎏) on the open-field behaviors and the thresholds and latency of nociceptive responses in adult rats. Results are as follows. 1) Capsaicin did not affect open-field behaviors. It hints that capsaicin did not alter the emotionality and motor function of rats. 2) Whereas the threshold of jumping was elevated, those of fore and hind paw licking were not in animals treated with capsaicin. Capsaicin also enhanced hind paw licking latency to thermal stimulus over thershold in hot plate test. These results suggest that capsaicin affects the coping reaction to strong thermal stimulus, but not adaptive reaction to mild stimulus, in adult rats.

Capsaicin 사전 투여에 의한 흰쥐의 공격성 감소 및 자율적 체온조절의 결손

박순권,홍승길,나흥식,김현택 한국심리학회 한국심리학회지 생물 및 생리 Vol.7 No.1

capsaicin 사전 처치가 흰쥐의 공격성과 체온조절에 미치는 영향을 알아보았다. 생후 6주경에 capsaicin을 피하주사하였고, 완전히 성숙한 후에 공격성 및 체온조절 기능을 검사하였다. 실험 1의 공격성 검사 결과 capsaicin 처치동물들의 공격성은 통제동물보다 낮았는데, 이것은 선행 연구의 결과와 상반된다. 체온조절 기능을 알아본 실험 2에서는 capsaicin 처치동물들이 37℃ 및 40℃ 조건에서 과체온과 빠른 체온증가를 보여주었다. 이것은 출생 직후 또는 성숙한 후에 약물을 투여한 선행연구들과 일치되는 결과이다. 따라서 capsaicin이 체온조절에 미치는 영향은 투여 시기와 무관한 것 같다. 논의에서는 본 연구의 두 가지 결과를 시상하부와 관련시켜 해석하였다. The present study was designed to examine effects of capsaicin administration on aggressive behaviors and autonomic thermoregulation in rats. In six-week-old rat, capsaicin was injected subcutaneously on 4 consecutive days in increasing doses(20㎎/㎏, 30㎎/㎏, 30㎎/㎏, 50㎎/㎏) to total of 150㎎/㎏ of the drug. The controls were treated in the same way with vehicle alone. Two experments began six or eight weeks after the treatment. In experiment 1, isolation-induced agressive behaviors, scored a 10-min session in the dyadic situation, were significantly decreased by capsaicin pretreatment. This result was not in accord with the previous findings. In experiment 2, body temperature of the capsaicin-treated rats increased more than the control's at two amibient temperatures studied(37℃ and 40℃). Our result concerning thermoregulation supports the preceding studies that applied to the capsaicin-treated animals as neonate or adult. Thus, it is likely that the effect of capsaicin treatment on thermoregulation has nothing to do with the age of capsaicin injection. The capsaicin effects from this study were compared with hypothalamic lesion effects in the discussion part.

Adipose-derived stem cells decolonize skin Staphylococcus aureus by enhancing phagocytic activity of peripheral blood mononuclear cells in the atopic rats

Lee, Jaehee,Park, Leejin,Kim, Hyeyoung,Rho, Bong-il,Han, Rafael Taeho,Kim, Sewon,Kim, Hee Jin,Na, Heung Sik,Back, Seung Keun The Korean Society of Pharmacology 2022 The Korean Journal of Physiology & Pharmacology Vol.26 No.4

Staphylococcus aureus (S. aureus) is known to induce apoptosis of host immune cells and impair phagocytic clearance, thereby being pivotal in the pathogenesis of atopic dermatitis (AD). Adipose-derived stem cells (ASCs) exert therapeutic effects against inflammatory and immune diseases. In the present study, we investigated whether systemic administration of ASCs restores the phagocytic activity of peripheral blood mononuclear cells (PBMCs) and decolonizes cutaneous S. aureus under AD conditions. AD was induced by injecting capsaicin into neonatal rat pups. ASCs were extracted from the subcutaneous adipose tissues of naïve rats and administered to AD rats once a week for a month. Systemic administration of ASCs ameliorated AD-like symptoms, such as dermatitis scores, serum IgE, IFN-γ⁺/IL-4⁺ cell ratio, and skin colonization by S. aureus in AD rats. Increased FasL mRNA and annexin V⁺/7-AAD⁺ cells in the PBMCs obtained from AD rats were drastically reversed when co-cultured with ASCs. In contrast, both PBMCs and CD163⁺ cells bearing fluorescent zymosan particles significantly increased in AD rats treated with ASCs. Additionally, the administration of ASCs led to an increase in the mRNA levels of antimicrobial peptides, such as cathelicidin and β-defensin, in the skin of AD rats. Our results demonstrate that systemic administration of ASCs led to decolonization of S. aureus by attenuating apoptosis of immune cells in addition to restoring phagocytic activity. This contributes to the improvement of skin conditions in AD rats. Therefore, administration of ASCs may be helpful in the treatment of patients with intractable AD.

Are Spinal GABAergic Elements Related to the Manifestation of Neuropathic Pain in Rat?

Jaehee Lee,Seung Keun Back,Eun Jeong Lim,Gyu Chong Cho,Myung Ah Kim,Hee Jin Kim,Min Hee Lee,Heung Sik Na 대한생리학회-대한약리학회 2010 The Korean Journal of Physiology & Pharmacology Vol.14 No.2

Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these aims, we first analyzed the pain behaviors following the spinal administration of GABA antagonists (1Ռg bicuculline/rat and 5Ռg phaclofen/rat), agonists (1Ռg muscimol/rat and 0.5Ռg baclofen/rat) or GABA transporter (GAT) inhibitors (20Ռg NNC-711/rat and 1Ռg SNAP-5114/rat) into naïve or neuropathic animals. Then, using Western blotting, PCR or immunohistochemistry, we compared the quantities of spinal GABA, its synthesizing enzymes (GAD65, 67) and its receptors (GABA_A and GABA_B) and transporters (GAT-1, and -3) between two groups of rats with different severity of neuropathic pain following partial injury of tail-innervating nerves; the allodynic and non-allodynic groups. Intrathecal administration of GABA antagonists markedly lowered tail-withdrawal threshold in naïve animals, and GABA agonists or GAT inhibitors significantly attenuated neuropathic pain in nerve-injured animals. However, any quantitative changes in spinal GABAergic elements were not observed in both the allodynic and non-allodynic groups. These results suggest that although the impairment in spinal GABAergic inhibition may play a role in mediation of neuropathic pain, it is not accomplished by the quantitative change in spinal elements for GABAergic inhibition and therefore these elements are not related to the generation of neuropathic pain following peripheral nerve injury.

한약제내의 중금속 및 일반독극물에 관한연구

나흥식 ( Heung Sik Na ),한근철 ( Keun Chul Han ),전태준 ( Tae Jun Chun ) 국군의무사령부 1990 대한군진의학학술지 Vol.21 No.1

구심성 미주신경과 구심성 하심장 신경에 대한 전기자극이 호흡과 혈압에 미치는 영향

나흥식 고려대학교 의과대학 1987 고려대 의대 잡지 Vol.24 No.1

This experiment was performed to determine the influence on tachypnea evoked by coronary heart diseases with pain in itself or pulmonary congestion secondary to acute congestive heart failure in the anesthetized and vagotomized cats. The results are summarized as follows: 1. The impulse discharges of phrenic efferents resulted from electrical stimulation of the left inferior cardiac nerve were increased by the increment of rate of phrenic efferents during inspiration. These results indicate the hyperpnea that can be produced by excitation of afferent cardiac sympathetic nerve fibers. 2. Cardiac pain evoked by electrical stimulation increases the blood pressure. 3. Not only C fibers but also A delta fibers participated in the change of the respiration and blood pressure. 4. Activation of pulmonary stretch receptor produced apnea. 5. During cold nerve block, activation of J receptor and bronchial receptor caused tachypnea characterized by increased rate of respiration, increased expiratory reserve volume and decreased tidal volume.