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Sun Kwang Kim
Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea

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Review
Published: 31 May 2021 in Biomedicines
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Neuropathic pain is an intractable chronic pain, caused by damage to the somatosensory nervous system. To date, treatment for neuropathic pain has limited effects. For the development of efficient therapeutic methods, it is essential to fully understand the pathological mechanisms of neuropathic pain. Besides abnormal sensitization in the periphery and spinal cord, accumulating evidence suggests that neural plasticity in the brain is also critical for the development and maintenance of this pain. Recent technological advances in the measurement and manipulation of neuronal activity allow us to understand maladaptive plastic changes in the brain during neuropathic pain more precisely and modulate brain activity to reverse pain states at the preclinical and clinical levels. In this review paper, we discuss the current understanding of pathological neural plasticity in the four pain-related brain areas: the primary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray, and the basal ganglia. We also discuss potential treatments for neuropathic pain based on the modulation of neural plasticity in these brain areas.

ACS Style

Myeong Bak; Haney Park; Sun Kim. Neural Plasticity in the Brain during Neuropathic Pain. Biomedicines 2021, 9, 624 .

AMA Style

Myeong Bak, Haney Park, Sun Kim. Neural Plasticity in the Brain during Neuropathic Pain. Biomedicines. 2021; 9 (6):624.

Chicago/Turabian Style

Myeong Bak; Haney Park; Sun Kim. 2021. "Neural Plasticity in the Brain during Neuropathic Pain." Biomedicines 9, no. 6: 624.

Journal article
Published: 06 December 2020 in Toxins
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Vincristine is a vinca alkaloid anti-mitotic drug with a broad spectrum of effects on solid and hematologic cancers. The major dose-limiting factor of this anti-cancer regimen is painful peripheral neuropathy. However, no gold-standard analgesic option has been used clinically. In this study, we investigated the effects and mechanism of bee venom acupuncture (BVA) to alleviate peripheral neuropathic pain induced by repeated intraperitoneal infusions of vincristine (1 mg/kg/day, days 1–5 and 8–12) in rats. Subcutaneous injection with bee venom (BV, 1.0 mg/kg) at the ST36 acupoint ameliorated cold and mechanical hypersensitivity (i.e., aberrant withdrawal responses in acetone drop and von Frey hair tests, respectively). In vivo extracellular recording demonstrated that BVA inhibited cutaneous cold (acetone) and mechanical (brush, press, and pinch) stimuli-elicited abnormal hyperexcitation of the spinal wide dynamic range (WDR) neurons in vincristine-treated rats. In addition, the microinjection of lidocaine into the ipsilateral locus coeruleus or the antagonism of the spinal α2-adrenergic receptors clearly reversed the effects of BVA on cold and mechanical hypersensitivity, indicating a vital role of the descending noradrenergic modulation in analgesia. These findings suggest that BVA could be a potential therapeutic option for vincristine-induced peripheral neuropathy.

ACS Style

Daxian Li; Geehoon Chung; Sun Kwang Kim. The Involvement of Central Noradrenergic Pathway in the Analgesic Effect of Bee Venom Acupuncture on Vincristine-Induced Peripheral Neuropathy in Rats. Toxins 2020, 12, 775 .

AMA Style

Daxian Li, Geehoon Chung, Sun Kwang Kim. The Involvement of Central Noradrenergic Pathway in the Analgesic Effect of Bee Venom Acupuncture on Vincristine-Induced Peripheral Neuropathy in Rats. Toxins. 2020; 12 (12):775.

Chicago/Turabian Style

Daxian Li; Geehoon Chung; Sun Kwang Kim. 2020. "The Involvement of Central Noradrenergic Pathway in the Analgesic Effect of Bee Venom Acupuncture on Vincristine-Induced Peripheral Neuropathy in Rats." Toxins 12, no. 12: 775.

Journal article
Published: 28 September 2020 in Toxins
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Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α2-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 μg), or MDL-72222 (5-HT3 receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.

ACS Style

Daxian Li; Ju Hyuk Yoo; Sun Kwang Kim. Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice. Toxins 2020, 12, 620 .

AMA Style

Daxian Li, Ju Hyuk Yoo, Sun Kwang Kim. Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice. Toxins. 2020; 12 (10):620.

Chicago/Turabian Style

Daxian Li; Ju Hyuk Yoo; Sun Kwang Kim. 2020. "Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice." Toxins 12, no. 10: 620.

Journal article
Published: 28 September 2020 in eLife
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Climbing fibers (CFs) generate complex spikes (CS) and Ca2+ transients in cerebellar Purkinje cells (PCs), serving as instructive signals. The so-called 'all-or-none' character of CSs has been questioned since the CF burst was described. Although recent studies have indicated a sensory-driven enhancement of PC Ca2+ signals, how CF responds to sensory events and contributes to PC dendritic Ca2+ and CS remains unexplored. Here, single or simultaneous Ca2+ imaging of CFs and PCs in awake mice revealed the presynaptic CF Ca2+ amplitude encoded the sensory input’s strength and directly influenced post-synaptic PC dendritic Ca2+ amplitude. The sensory-driven variability in CF Ca2+ amplitude depended on the number of spikes in the CF burst. Finally, the spike number of the CF burst determined the PC Ca2+ influx and CS properties. These results reveal the direct translation of sensory information-coding CF inputs into PC Ca2+, suggesting the sophisticated role of CFs as error signals.

ACS Style

Seung-Eon Roh; Seung Ha Kim; Changhyeon Ryu; Chang-Eop Kim; Yong Gyu Kim; Paul F Worley; Sun Kwang Kim; Sang Jeong Kim. Direct translation of climbing fiber burst-mediated sensory coding into post-synaptic Purkinje cell dendritic calcium. eLife 2020, 9, 1 .

AMA Style

Seung-Eon Roh, Seung Ha Kim, Changhyeon Ryu, Chang-Eop Kim, Yong Gyu Kim, Paul F Worley, Sun Kwang Kim, Sang Jeong Kim. Direct translation of climbing fiber burst-mediated sensory coding into post-synaptic Purkinje cell dendritic calcium. eLife. 2020; 9 ():1.

Chicago/Turabian Style

Seung-Eon Roh; Seung Ha Kim; Changhyeon Ryu; Chang-Eop Kim; Yong Gyu Kim; Paul F Worley; Sun Kwang Kim; Sang Jeong Kim. 2020. "Direct translation of climbing fiber burst-mediated sensory coding into post-synaptic Purkinje cell dendritic calcium." eLife 9, no. : 1.

Preprint content
Published: 30 June 2020
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We developed AI-bRNN (Average training, Individual test-bidirectional Recurrent Neural Network) to decipher spontaneous pain information from brain cellular calcium signals recorded by two-photon imaging in awake, head-fixed mice. The AI-bRNN determines the intensity and time point of spontaneous pain even during the chronic pain period and evaluates the efficacy of analgesics. Furthermore, it could be applied to different cell types and brain areas, and it distinguished between itch and pain, proving its versatility.

ACS Style

Heera Yoon; Myeong Seong Bak; Seung Ha Kim; Ji Hwan Lee; Geehoon Chung; Sang Jeong Kim; Sun Kwang Kim. Decoding spontaneous pain from brain cellular calcium signals using deep learning. 2020, 1 .

AMA Style

Heera Yoon, Myeong Seong Bak, Seung Ha Kim, Ji Hwan Lee, Geehoon Chung, Sang Jeong Kim, Sun Kwang Kim. Decoding spontaneous pain from brain cellular calcium signals using deep learning. . 2020; ():1.

Chicago/Turabian Style

Heera Yoon; Myeong Seong Bak; Seung Ha Kim; Ji Hwan Lee; Geehoon Chung; Sang Jeong Kim; Sun Kwang Kim. 2020. "Decoding spontaneous pain from brain cellular calcium signals using deep learning." , no. : 1.

Journal article
Published: 19 August 2019 in Toxins
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Bee venom (BV) has a long history of being used in traditional Korean medicine to relieve pain. Here, we investigated the effect of BV-derived phospholipase A2 (bvPLA2), a major component of BV, on peripheral nerve injury-induced neuropathic pain in rats. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to induce neuropathic pain, and paw withdrawal thresholds were measured using von Frey test. Mechanical allodynia, the representative symptom of neuropathic pain, was manifested following SNL and persisted for several weeks. The repetitive bvPLA2 treatment (0.2 mg/kg/day, i.p.) for two days significantly relieved the SNL-induced mechanical allodynia. The antiallodynic effect of bvPLA2 was blocked by spinal pretreatment with α1-adrenergic antagonist prazosin (30 μg, i.t.) but not with α2-adrenergic antagonist idazoxan (50 μg, i.t.). Also, the spinal application of α1-adrenergic agonist phenylephrine (50 μg, i.t.) reduced mechanical allodynia. These results indicate that bvPLA2 could relieve nerve injury-induced neuropathic mechanical allodynia through the activation of spinal α1-adrenergic receptors.

ACS Style

SeungHui Woo; Geehoon Chung; Hyunsu Bae; Sun Kwang Kim. Suppressive Effects of Bee Venom-Derived Phospholipase A2 on Mechanical Allodynia in a Rat Model of Neuropathic Pain. Toxins 2019, 11, 477 .

AMA Style

SeungHui Woo, Geehoon Chung, Hyunsu Bae, Sun Kwang Kim. Suppressive Effects of Bee Venom-Derived Phospholipase A2 on Mechanical Allodynia in a Rat Model of Neuropathic Pain. Toxins. 2019; 11 (8):477.

Chicago/Turabian Style

SeungHui Woo; Geehoon Chung; Hyunsu Bae; Sun Kwang Kim. 2019. "Suppressive Effects of Bee Venom-Derived Phospholipase A2 on Mechanical Allodynia in a Rat Model of Neuropathic Pain." Toxins 11, no. 8: 477.

Journal article
Published: 08 July 2019 in Toxins
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Oxaliplatin is a chemotherapeutic agent used for metastatic colon and other advanced cancers. Most common side effect of oxaliplatin is peripheral neuropathy, manifested in mechanical and cold allodynia. Although the analgesic effect of bee venom has been proven to be effective against oxaliplatin-induced peripheral neuropathy, the effect of its major component; melittin has not been studied yet. Thus, in this study, we investigated whether melittin has an analgesic effect on oxaliplatin-induced allodynia. Intraperitoneal single injection of oxaliplatin (6 mg/kg) induced mechanical and cold allodynia, resulting in increased withdrawal behavior in response to von Frey filaments and acetone drop on hind paw. Subcutaneous melittin injection on acupoint ST36 (0.5 mg/kg) alleviated oxaliplatin-induced mechanical and cold allodynia. In electrophysiological study, using spinal in vivo extracellular recording, it was shown that oxaliplatin-induced hyperexcitation of spinal wide dynamic range neurons in response to peripheral stimuli, and melittin administration inhibited this neuronal activity. In behavioral assessment, analgesic effect of melittin was blocked by intrathecal α1- and α2- adrenergic receptor antagonists administration. Based on these results, we suggest that melittin could be used as an analgesic on oxaliplatin-induced peripheral neuropathy, and that its effect is mediated by activating the spinal α1- and α2-adrenergic receptors.

ACS Style

Seunghwan Choi; Hyeon Kyeong Chae; Ho Heo; Dae-Hyun Hahm; Woojin Kim; Sun Kwang Kim. Analgesic Effect of Melittin on Oxaliplatin-Induced Peripheral Neuropathy in Rats. Toxins 2019, 11, 396 .

AMA Style

Seunghwan Choi, Hyeon Kyeong Chae, Ho Heo, Dae-Hyun Hahm, Woojin Kim, Sun Kwang Kim. Analgesic Effect of Melittin on Oxaliplatin-Induced Peripheral Neuropathy in Rats. Toxins. 2019; 11 (7):396.

Chicago/Turabian Style

Seunghwan Choi; Hyeon Kyeong Chae; Ho Heo; Dae-Hyun Hahm; Woojin Kim; Sun Kwang Kim. 2019. "Analgesic Effect of Melittin on Oxaliplatin-Induced Peripheral Neuropathy in Rats." Toxins 11, no. 7: 396.

Original research article
Published: 05 April 2019 in Frontiers in Cellular Neuroscience
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The primary somatosensory (S1) cortex plays an important role in the perception and discrimination of touch and pain mechanosensations. Conventionally, neurons in the somatosensory system including S1 cortex have been classified into low/high threshold (HT; non-nociceptive/nociceptive) or wide dynamic range (WDR; convergent) neurons by their electrophysiological responses to innocuous brush-stroke and noxious forceps-pinch stimuli. Besides this “noxiousness” (innocuous/noxious) feature, each stimulus also includes other stimulus features: “texture” (brush hairs/forceps-steel arm), “dynamics” (dynamic stroke/static press) and “intensity” (weak/strong). However, it remains unknown how S1 neurons inclusively process such diverse features of brushing and pinch at the single-cell and population levels. Using in vivo two-photon Ca2+ imaging in the layer 2/3 neurons of the mouse S1 cortex, we identified clearly separated response patterns of the S1 neural population with distinct tuning properties of individual cells to texture, dynamics and noxiousness features of cutaneous mechanical stimuli. Among cells other than broadly tuned neurons, the majority of the cells showed a highly selective response to the difference in texture, but low selectivity to the difference in dynamics or noxiousness. Between the two low selectivity features, the difference in dynamics was slightly more specific, yet both could be decoded using the response patterns of neural populations. In addition, more neurons are recruited and stronger Ca2+ responses are evoked as the intensity of forceps-pinch is gradually increased. Our results suggest that S1 neurons encode various features of mechanosensations with feature-dependent differential selectivity of single cells and distributed response patterns of populations. Moreover, we raise a caution about describing neurons by a single stimulus feature ignoring other aspects of the sensory stimuli.

ACS Style

Yoo Rim Kim; Chang-Eop Kim; Heera Yoon; Sun Kwang Kim; Sang Jeong Kim. S1 Employs Feature-Dependent Differential Selectivity of Single Cells and Distributed Patterns of Populations to Encode Mechanosensations. Frontiers in Cellular Neuroscience 2019, 13, 1 .

AMA Style

Yoo Rim Kim, Chang-Eop Kim, Heera Yoon, Sun Kwang Kim, Sang Jeong Kim. S1 Employs Feature-Dependent Differential Selectivity of Single Cells and Distributed Patterns of Populations to Encode Mechanosensations. Frontiers in Cellular Neuroscience. 2019; 13 ():1.

Chicago/Turabian Style

Yoo Rim Kim; Chang-Eop Kim; Heera Yoon; Sun Kwang Kim; Sang Jeong Kim. 2019. "S1 Employs Feature-Dependent Differential Selectivity of Single Cells and Distributed Patterns of Populations to Encode Mechanosensations." Frontiers in Cellular Neuroscience 13, no. : 1.

Journal article
Published: 03 April 2019 in International Journal of Molecular Sciences
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The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the α2-adrenergic antagonist idazoxan (10 μg, i.t.), but not the α1-adrenergic antagonist prazosin (10 μg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT3 receptor antagonist bemesetron (MDL-72222, 15 μg, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 μg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α2-adrenergic receptor, and both α2-adrenergic and 5-HT3 receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.

ACS Style

Daxian Li; Ji Hwan Lee; Chang Won Choi; Jaihwan Kim; Sun Kwang Kim; Woojin Kim. The Analgesic Effect of Venlafaxine and Its Mechanism on Oxaliplatin-Induced Neuropathic Pain in Mice. International Journal of Molecular Sciences 2019, 20, 1652 .

AMA Style

Daxian Li, Ji Hwan Lee, Chang Won Choi, Jaihwan Kim, Sun Kwang Kim, Woojin Kim. The Analgesic Effect of Venlafaxine and Its Mechanism on Oxaliplatin-Induced Neuropathic Pain in Mice. International Journal of Molecular Sciences. 2019; 20 (7):1652.

Chicago/Turabian Style

Daxian Li; Ji Hwan Lee; Chang Won Choi; Jaihwan Kim; Sun Kwang Kim; Woojin Kim. 2019. "The Analgesic Effect of Venlafaxine and Its Mechanism on Oxaliplatin-Induced Neuropathic Pain in Mice." International Journal of Molecular Sciences 20, no. 7: 1652.

Journal article
Published: 19 February 2019 in Nutrients
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A chemotherapy drug, oxaliplatin, induces cold and mechanical hypersensitivity, but effective treatments for this neuropathic pain without side effects are still lacking. We previously showed that Cinnamomi Cortex suppresses oxaliplatin-induced pain behaviors in rats. However, it remains unknown which phytochemical of Cinnamomi Cortex plays a key role in that analgesic action. Thus, here we investigated whether and how cinnamic acid or cinnamaldehyde, major components of Cinnamomi Cortex, alleviates cold and mechanical allodynia induced by a single oxaliplatin injection (6 mg/kg, i.p.) in rats. Using an acetone test and the von Frey test for measuring cold and mechanical allodynia, respectively, we found that administration of cinnamic acid, but not cinnamaldehyde, at doses of 10, 20 and 40 mg/kg (i.p.) significantly attenuates the allodynic behaviors in oxaliplatin-injected rats with the strongest effect being observed at 20 mg/kg. Our in vivo extracellular recordings also showed that cinnamic acid (20 mg/kg, i.p.) inhibits the increased activities of spinal wide dynamic range neurons in response to cutaneous mechanical and cold stimuli following the oxaliplatin injection. These results indicate that cinnamic acid has an effective analgesic action against oxaliplatin-induced neuropathic pain through inhibiting spinal pain transmission, suggesting its crucial role in mediating the effect of Cinnamomi Cortex.

ACS Style

Hyeon Kyeong Chae; Woojin Kim; Sun Kwang Kim. Phytochemicals of Cinnamomi Cortex: Cinnamic Acid, but not Cinnamaldehyde, Attenuates Oxaliplatin-Induced Cold and Mechanical Hypersensitivity in Rats. Nutrients 2019, 11, 432 .

AMA Style

Hyeon Kyeong Chae, Woojin Kim, Sun Kwang Kim. Phytochemicals of Cinnamomi Cortex: Cinnamic Acid, but not Cinnamaldehyde, Attenuates Oxaliplatin-Induced Cold and Mechanical Hypersensitivity in Rats. Nutrients. 2019; 11 (2):432.

Chicago/Turabian Style

Hyeon Kyeong Chae; Woojin Kim; Sun Kwang Kim. 2019. "Phytochemicals of Cinnamomi Cortex: Cinnamic Acid, but not Cinnamaldehyde, Attenuates Oxaliplatin-Induced Cold and Mechanical Hypersensitivity in Rats." Nutrients 11, no. 2: 432.

Mini review article
Published: 08 October 2018 in Frontiers in Molecular Neuroscience
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Pain and depression affect one another, and this bidirectional interaction implies the existence of common or interacting neural pathways. Among the neural circuits relevant to negative affection, the medial prefrontal cortex (mPFC) is known to be involved in both pain and depression. Persistent stress from physical pain and mental distress can evoke maladaptive changes in mPFC circuits to induce depression. Conversely, the unpleasant mood condition alters mPFC circuits to distort the appraisal of aversion and make individuals vulnerable to pain. In this article, recent findings regarding mPFC in chronic pain and/or depression are reviewed, with particular focus on the metabotropic glutamate receptor 5 (mGluR5). Although the involvement of mGluR5 within the mPFC in both pain and depressive disorders has been extensively studied, there are controversies regarding changes in the activity of the mPFC during chronic pain and depression, and the functional roles of mGluR5 on altered mPFC activity. We discuss alterations in the availability of mGluR5 in the mPFC in these disorders, its role in behavioral manifestations, and its possible influence on cellular subpopulations that mediate dysfunction in the mPFC. We also propose molecular mechanisms that may cause expressional changes in mGluR5 within the mPFC circuitry.

ACS Style

Geehoon Chung; Sang Jeong Kim; Sun Kwang Kim. Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex as a Molecular Determinant of Pain and Ensuing Depression. Frontiers in Molecular Neuroscience 2018, 11, 376 .

AMA Style

Geehoon Chung, Sang Jeong Kim, Sun Kwang Kim. Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex as a Molecular Determinant of Pain and Ensuing Depression. Frontiers in Molecular Neuroscience. 2018; 11 ():376.

Chicago/Turabian Style

Geehoon Chung; Sang Jeong Kim; Sun Kwang Kim. 2018. "Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex as a Molecular Determinant of Pain and Ensuing Depression." Frontiers in Molecular Neuroscience 11, no. : 376.

Journal article
Published: 05 December 2017 in International Journal of Molecular Sciences
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Oxaliplatin is a widely used chemotherapy agent, but induces serious peripheral neuropathy. Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine, and is shown to be effective against pain. However, whether and how duloxetine can attenuate oxaliplatin-induced allodynia in rodents is not clearly understood. A single injection of oxaliplatin (6 mg/kg, intraperitoneal; i.p.) induced a cold and mechanical allodynia, which was assessed by acetone and von Frey filament tests, respectively. When significant allodynic signs were observed, three different doses of duloxetine (10, 30, and 60 mg/kg, i.p.) were injected. Administration of 30 and 60 mg/kg of duloxetine significantly reduced the allodynia, whereas 10 mg/kg did not. By using an in vivo extracellular recording method, we further confirmed that 30 mg/kg of duloxetine could significantly inhibit the hyperexcitability of spinal wide dynamic range (WDR) cells. The anti-allodynic effect of duloxetine was completely blocked by an intrathecal injection of phentolamine (non-selective α-adrenergic receptor antagonist, 20 μg), or prazosin (α1-adrenergic receptor antagonists, 10 μg); however, idazoxan (α2-adrenergic receptor antagonist, 10 μg) did not block it. In conclusion, we suggest that duloxetine may have an effective protective action against oxaliplatin-induced neuropathic pain and spinal hyperexcitability, which is mediated by spinal α1-adrenergic receptors.

ACS Style

Woojin Kim; Yeongu Chung; Seunghwan Choi; Byung-Il Min; Sun Kwang Kim. Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents. International Journal of Molecular Sciences 2017, 18, 2626 .

AMA Style

Woojin Kim, Yeongu Chung, Seunghwan Choi, Byung-Il Min, Sun Kwang Kim. Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents. International Journal of Molecular Sciences. 2017; 18 (12):2626.

Chicago/Turabian Style

Woojin Kim; Yeongu Chung; Seunghwan Choi; Byung-Il Min; Sun Kwang Kim. 2017. "Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents." International Journal of Molecular Sciences 18, no. 12: 2626.

Journal article
Published: 31 October 2017 in Toxins
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Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α2-adrenergic receptor antagonist (idazoxan, 50 µg), but not α1-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α2-adrenergic receptor.

ACS Style

Jiho Choi; Changhoon Jeon; Ji Hwan Lee; Jo Ung Jang; Fu Shi Quan; Kyungjin Lee; Woojin Kim; Sun Kwang Kim. Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α2-Adrenergic Receptor. Toxins 2017, 9, 351 .

AMA Style

Jiho Choi, Changhoon Jeon, Ji Hwan Lee, Jo Ung Jang, Fu Shi Quan, Kyungjin Lee, Woojin Kim, Sun Kwang Kim. Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α2-Adrenergic Receptor. Toxins. 2017; 9 (11):351.

Chicago/Turabian Style

Jiho Choi; Changhoon Jeon; Ji Hwan Lee; Jo Ung Jang; Fu Shi Quan; Kyungjin Lee; Woojin Kim; Sun Kwang Kim. 2017. "Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α2-Adrenergic Receptor." Toxins 9, no. 11: 351.

Review
Published: 06 April 2017 in Journal of Neurochemistry
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Tissue or nerve injury induces widespread plastic changes from the periphery and spinal cord up to the cortex, resulting in chronic pain. Although many clinicians and researchers have extensively studied altered nociceptive signaling and neural circuit plasticity at the spinal cord level, effective treatments to ameliorate chronic pain are still insufficient. For about the last two decades, the rapid development in macroscopic brain imaging studies on humans and animal models have revealed maladaptive plastic changes in the ‘pain matrix’ brain regions, which may subsequently contribute to chronic pain. Among these brain regions, our group has concentrated for many years on the primary somatosensory (S1) cortex with a help of advanced imaging techniques and has found the functional and structural changes in neurons/glia as well as individual synapses in the S1 cortex during chronic pain. Taken together, it is now believed that such S1 plasticity is one of the causes for chronic pain, not a simple and passive epiphenomenon following tissue/nerve injury as previously thought. In this small review, we discuss the relation of plasticity in the S1 cortex with chronic pain, based on clinical trials and experimental studies conducted on this field. This article is part of the special article series “Pain”.

ACS Style

Woojin Kim; Sun Kwang Kim; Junichi Nabekura. Functional and structural plasticity in the primary somatosensory cortex associated with chronic pain. Journal of Neurochemistry 2017, 141, 499 -506.

AMA Style

Woojin Kim, Sun Kwang Kim, Junichi Nabekura. Functional and structural plasticity in the primary somatosensory cortex associated with chronic pain. Journal of Neurochemistry. 2017; 141 (4):499-506.

Chicago/Turabian Style

Woojin Kim; Sun Kwang Kim; Junichi Nabekura. 2017. "Functional and structural plasticity in the primary somatosensory cortex associated with chronic pain." Journal of Neurochemistry 141, no. 4: 499-506.

Journal article
Published: 14 January 2017 in BMC Complementary and Alternative Medicine
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Oxaliplatin, a widely used anticancer drug against metastatic colorectal cancer, can induce acute peripheral neuropathy, which is characterized by cold and mechanical allodynia. Activation of glial cells (e.g. astrocytes and microglia) and increase of pro-inflammatory cytokines (e.g. IL-1β and TNF-α) in the spinal cord play a crucial role in the pathogenesis of neuropathic pain. Our previous study demonstrated that Gyejigachulbu-Tang (GBT), a herbal complex formula, alleviates oxaliplatin-induced neuropathic pain in rats by suppressing spinal glial activation. However, it remains to be elucidated whether and how Buja (Aconiti Tuber), a major ingredient of GBT, is involved in the efficacy of GBT. Cold and mechanical allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) in Sprauge-Dawley rats were evaluated by a tail immersion test in cold water (4 °C) and a von Frey hair test, respectively. Buja (300 mg/kg) was orally administrated for five consecutive days after the oxaliplatin injection. Glial activation in the spinal cord was quantified by immunohistochemical staining using GFAP (for astrocytes) and Iba-1 (for microglia) antibodies. The amount of spinal pro-inflammatory cytokines, IL-1β and TNF-α, were measured by ELISA. Significant behavioral signs of cold and mechanical allodynia were observed 3 days after an oxaliplatin injection. Oral administration of Buja significantly alleviated oxaliplatin-induced cold and mechanical allodynia by increasing the tail withdrawal latency to cold stimuli and mechanical threshold. Immunohistochemical analysis showed the activation of astrocytes and microglia and the increase of the IL-1β and TNF-α levels in the spinal cord after an oxaliplatin injection. Administration of Buja suppressed the activation of spinal astrocytes without affecting microglial activation and down-regulated both IL-1β and TNF-α levels in the spinal cord. Our results indicate that Buja has a potent anti-allodynic effect in a rat model of oxaliplatin-induced neuropathic pain, which is associated with the inhibition of activation of astrocytes and release of pro-inflammatory cytokines in the spinal cord. Thus, our findings suggest that administration of Buja could be an alternative therapeutic option for the management of peripheral neuropathy, a common side-effect of oxaliplatin.

ACS Style

Yongjae Jung; Ji Hwan Lee; Woojin Kim; Sang Hyub Yoon; Sun Kwang Kim. Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression. BMC Complementary and Alternative Medicine 2017, 17, 1 -8.

AMA Style

Yongjae Jung, Ji Hwan Lee, Woojin Kim, Sang Hyub Yoon, Sun Kwang Kim. Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression. BMC Complementary and Alternative Medicine. 2017; 17 (1):1-8.

Chicago/Turabian Style

Yongjae Jung; Ji Hwan Lee; Woojin Kim; Sang Hyub Yoon; Sun Kwang Kim. 2017. "Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression." BMC Complementary and Alternative Medicine 17, no. 1: 1-8.

Short communication
Published: 28 November 2016 in The Journal of Physiological Sciences
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We investigated the spinal action of noradrenaline on cold-elicited hyperexcitation detected in dorsal horn neurons of rats with allodynia induced by an oxaliplatin (6 mg/kg, i.p.) injection. In vivo extracellular recordings from the spinal dorsal horn showed that wide dynamic range neurons responded to cutaneous acetone (10 μl) stimulation in normal rats, and cold-elicited firings in oxaliplatin-administered rats were increased with a longer duration, correlated with behavioral responses. These responses were significantly attenuated by spinal administration (50 μM) of noradrenaline or its agonists, clonidine (α2), phenylephrine (α1) and isoprenaline (β), in descending order of efficacy. Thus, the inhibitory effect of noradrenaline on spinal oxaliplatin-induced cold hyperexcitation is mediated mainly by activation of α2- and/or α1-adrenoceptors.

ACS Style

Seunghwan Choi; Akihiro Yamada; Woojin Kim; Sun Kwang Kim; Hidemasa Furue. Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: electrophysiological and behavioral assessments. The Journal of Physiological Sciences 2016, 67, 431 -438.

AMA Style

Seunghwan Choi, Akihiro Yamada, Woojin Kim, Sun Kwang Kim, Hidemasa Furue. Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: electrophysiological and behavioral assessments. The Journal of Physiological Sciences. 2016; 67 (3):431-438.

Chicago/Turabian Style

Seunghwan Choi; Akihiro Yamada; Woojin Kim; Sun Kwang Kim; Hidemasa Furue. 2016. "Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: electrophysiological and behavioral assessments." The Journal of Physiological Sciences 67, no. 3: 431-438.

Review
Published: 20 September 2016 in Molecules
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Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse effect of neurotoxic anticancer medicines. It leads to autonomic and somatic system dysfunction and decreases the patient’s quality of life. This side effect eventually causes chemotherapy non-compliance. Patients are prompted to seek alternative treatment options since there is no conventional remedy for CIPN. A range of medicinal herbs have multifarious effects, and they have shown some evidence of efficacy in various neurological and immunological diseases. While CIPN has multiple mechanisms of neurotoxicity, these phytomedicines might offer neuronal protection or regeneration with the multiple targets in CIPN. Thus far, researchers have investigated the therapeutic benefits of several herbs, herbal formulas, and phytochemicals in preventing the onset and progress of CIPN in animals and humans. Here, we summarize current knowledge regarding the role of phytochemicals, herb extracts, and herbal formulas in alleviating CIPN.

ACS Style

Gihyun Lee; Sun Kwang Kim. Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy. Molecules 2016, 21, 1252 .

AMA Style

Gihyun Lee, Sun Kwang Kim. Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy. Molecules. 2016; 21 (9):1252.

Chicago/Turabian Style

Gihyun Lee; Sun Kwang Kim. 2016. "Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy." Molecules 21, no. 9: 1252.

Journal article
Published: 20 September 2016 in Molecules
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Oxaliplatin, a chemotherapy drug, induces acute peripheral neuropathy characterized by cold allodynia, spinal glial activation and increased levels of pro-inflammatory cytokines. Herein, we determined whether Cinnamomi Cortex (C. Cortex), a widely used medicinal herb in East Asia for cold-related diseases, could attenuate oxaliplatin-induced cold allodynia in rats and the mechanisms involved. A single oxaliplatin injection (6 mg/kg, i.p.) induced significant cold allodynia signs based on tail immersion tests using cold water (4 °C). Daily oral administration of water extract of C. Cortex (WECC) (100, 200, and 400 mg/kg) for five consecutive days following an oxaliplatin injection dose-dependently alleviated cold allodynia with only a slight difference in efficacies between the middle dose at 200 mg/kg and the highest dose at 400 mg/kg. WECC at 200 mg/kg significantly suppressed the activation of astrocytes and microglia and decreased the expression levels of IL-1β and TNF in the spinal cord after injection with oxaliplatin. Furthermore, oral administration of coumarin (10 mg/kg), a major phytocompound of C. Cortex, markedly reduced cold allodynia. These results indicate that C. Cortex has a potent anti-allodynic effect in oxaliplatin-injected rats through inhibiting spinal glial cells and pro-inflammatory cytokines. We also suggest that coumarin might play a role in the anti-allodynic effect of C. Cortex.

ACS Style

Changmin Kim; Ji Hwan Lee; Woojin Kim; Dongxing Li; Yangseok Kim; Kyungjin Lee; Sun Kwang Kim. The Suppressive Effects of Cinnamomi Cortex and Its Phytocompound Coumarin on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats. Molecules 2016, 21, 1253 .

AMA Style

Changmin Kim, Ji Hwan Lee, Woojin Kim, Dongxing Li, Yangseok Kim, Kyungjin Lee, Sun Kwang Kim. The Suppressive Effects of Cinnamomi Cortex and Its Phytocompound Coumarin on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats. Molecules. 2016; 21 (9):1253.

Chicago/Turabian Style

Changmin Kim; Ji Hwan Lee; Woojin Kim; Dongxing Li; Yangseok Kim; Kyungjin Lee; Sun Kwang Kim. 2016. "The Suppressive Effects of Cinnamomi Cortex and Its Phytocompound Coumarin on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats." Molecules 21, no. 9: 1253.

Journal article
Published: 11 April 2016 in Journal of Clinical Investigation
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Long-term treatments to ameliorate peripheral neuropathic pain that includes mechanical allodynia are limited. While glial activation and altered nociceptive transmission within the spinal cord are associated with the pathogenesis of mechanical allodynia, changes in cortical circuits also accompany peripheral nerve injury and may represent additional therapeutic targets. Dendritic spine plasticity in the S1 cortex appears within days following nerve injury; however, the underlying cellular mechanisms of this plasticity and whether it has a causal relationship to allodynia remain unsolved. Furthermore, it is not known whether glial activation occurs within the S1 cortex following injury or whether it contributes to this S1 synaptic plasticity. Using in vivo 2-photon imaging with genetic and pharmacological manipulations of murine models, we have shown that sciatic nerve ligation induces a re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astroglia, which elicits spontaneous somatic Ca2+ transients, synaptogenic thrombospondin 1 (TSP-1) release, and synapse formation. This S1 astrocyte reactivation was evident only during the first week after injury and correlated with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover. Blocking the astrocytic mGluR5-signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of any peripheral injury induced long-lasting (>1 month) allodynia. We conclude that reawakened astrocytes are a key trigger for S1 circuit rewiring and that this contributes to neuropathic mechanical allodynia.

ACS Style

Sun Kwang Kim; Hideaki Hayashi; Tatsuya Ishikawa; Keisuke Shibata; Eiji Shigetomi; Youichi Shinozaki; Hiroyuki Inada; Seung Eon Roh; Sang Jeong Kim; Gihyun Lee; Hyunsu Bae; Andrew Moorhouse; Katsuhiko Mikoshiba; Yugo Fukazawa; Schuichi Koizumi; Junichi Nabekura. Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. Journal of Clinical Investigation 2016, 126, 1983 -1997.

AMA Style

Sun Kwang Kim, Hideaki Hayashi, Tatsuya Ishikawa, Keisuke Shibata, Eiji Shigetomi, Youichi Shinozaki, Hiroyuki Inada, Seung Eon Roh, Sang Jeong Kim, Gihyun Lee, Hyunsu Bae, Andrew Moorhouse, Katsuhiko Mikoshiba, Yugo Fukazawa, Schuichi Koizumi, Junichi Nabekura. Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. Journal of Clinical Investigation. 2016; 126 (5):1983-1997.

Chicago/Turabian Style

Sun Kwang Kim; Hideaki Hayashi; Tatsuya Ishikawa; Keisuke Shibata; Eiji Shigetomi; Youichi Shinozaki; Hiroyuki Inada; Seung Eon Roh; Sang Jeong Kim; Gihyun Lee; Hyunsu Bae; Andrew Moorhouse; Katsuhiko Mikoshiba; Yugo Fukazawa; Schuichi Koizumi; Junichi Nabekura. 2016. "Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain." Journal of Clinical Investigation 126, no. 5: 1983-1997.

Journal article
Published: 22 January 2016 in Toxins
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Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2-adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

ACS Style

Woojin Kim; Min Joon Kim; Donghyun Go; Byung-Il Min; Heung Sik Na; Sun Kwang Kim. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice. Toxins 2016, 8, 33 .

AMA Style

Woojin Kim, Min Joon Kim, Donghyun Go, Byung-Il Min, Heung Sik Na, Sun Kwang Kim. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice. Toxins. 2016; 8 (2):33.

Chicago/Turabian Style

Woojin Kim; Min Joon Kim; Donghyun Go; Byung-Il Min; Heung Sik Na; Sun Kwang Kim. 2016. "Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice." Toxins 8, no. 2: 33.