• The Korean Journal of Physiology and Pharmacology
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• v.27 no.1
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• pp.39-48
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• 2023

Spinal nerve injury causes mechanical allodynia and structural imbalance of neurotransmission, which were typically associated with calcium overload. Storeoperated calcium entry (SOCE) is considered crucial elements-mediating intracellular calcium homeostasis, ion channel activity, and synaptic plasticity. However, the underlying mechanism of SOCE in mediating neuronal transmitter release and synaptic transmission remains ambiguous in neuropathic pain. Neuropathic rats were operated by spinal nerve ligations. Neurotransmissions were assessed by whole-cell recording in substantia gelatinosa. Immunofluorescence staining of STIM1 with neuronal and glial biomarkers in the spinal dorsal horn. The endoplasmic reticulum stress level was estimated from qRT-PCR. Intrathecal injection of SOCE antagonist SKF96365 dose-dependently alleviated mechanical allodynia in ipsilateral hind paws of neuropathic rats with ED₅₀ of 18 ㎍. Immunofluorescence staining demonstrated that STIM1 was specifically and significantly expressed in neurons but not astrocytes and microglia in the spinal dorsal horn. Bath application of SKF96365 inhibited enhanced miniature excitatory postsynaptic currents in a dosage-dependent manner without affecting miniature inhibitory postsynaptic currents. Mal-adaption of SOCE was commonly related to endoplasmic reticulum (ER) stress in the central nervous system. SKF96365 markedly suppressed ER stress levels by alleviating mRNA expression of C/ EBP homologous protein and heat shock protein 70 in neuropathic rats. Our findings suggested that nerve injury might promote SOCE-mediated calcium levels, resulting in long-term imbalance of spinal synaptic transmission and behavioral sensitization, SKF96365 produces antinociception by alleviating glutamatergic transmission and ER stress. This work demonstrated the involvement of SOCE in neuropathic pain, implying that SOCE might be a potential target for pain management.

• The Korean Journal of Pain
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• v.36 no.1
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• pp.137-246
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• 2023

Background: To investigate the relationship between cutaneous allodynia (CA) and kinesiophobia, gastrointestinal system (GIS) symptom severity, physical activity, and disability, and to determine whether CA, pain, and disability were influencing factors for kinesiophobia, GIS symptoms, and physical activity in individuals with migraine. Methods: The study included 144 individuals with migraine. CA, kinesiophobia, GIS symptoms, physical activity level, and migraine-related disability were evaluated with the Allodynia Symptom Checklist, the Tampa Kinesiophobia Scale (TKS), the Gastrointestinal Symptom Rating Scale (GSRS), the International Physical Activity Questionnaire-7, and the Migraine Disability Assessment Scale (MIDAS), respectively. Results: The CA severity was only associated with TKS (r = 0.515; P < 0.001), GSRS-total (r = 0.336; P < 0.001), GSRS-abdominal pain (r = 0.323; P < 0.001), GSRS-indigestion (r = 0.257; P = 0.002), GSRS-constipation (r = 0.371; P < 0.001), and MIDAS scores (r = 0.178; P = 0.033). Attack frequency (P = 0.015), attack duration (P = 0.035) and presence of CA (P < 0.001) were risk factors for kinesiophobia. Attack frequency (P = 0.027) and presence of CA (P = 0.004) were risk factors for GIS symptoms. Conclusions: There was a relationship between the CA and kinesiophobia, GIS symptoms, and disability. CA and attack frequency were found to be risk factors for kinesiophobia and GIS symptoms. Migraine patients with CA should be assessed in terms of kinesiophobia, GIS, and disability. Lifestyle changes such as exercise and dietary changes and/or pharmacological treatment options for CA may increase success in migraine management.

• The Korean Journal of Pain
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• v.36 no.1
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• pp.51-59
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• 2023

Background: This study investigated the effect of an excess and a deficit of spinal 5-hydroxytryptamine (5-HT) on the mechanical allodynia and neuroglia activation in a rodent pain model of carrageenan inflammation. Methods: Male Sprague-Dawley rats were implanted with an intrathecal (i.t.) catheter to administer the drug. To induce an excess or deficit of 5-HT in the spinal cord, animals were given either three i.t. 5-HT injections at 24-hour intervals or a single i.t. injection of 5,7-dihydroxytryptamine (5,7-DHT) before carrageenan inflammation. Mechanical allodynia was measured using the von Frey test for 0-4 hours (early phase) and 24-28 hours (late phase) after carrageenan injection. The changes in the activation of microglia and astrocyte were examined using immunofluorescence of the dorsal horn of the lumbar spinal cord. Results: Both an excess and a deficit of spinal 5-HT had no or a minimal effect on the intensity of mechanical allodynia during the early phase but prevented the attenuation of mechanical allodynia during the late phase, which was observed in animals not treated with i.t. 5-HT or 5,7-DHT. Animals with an excess or deficit of 5-HT showed stronger activation of microglia, but not astrocyte, during the early and late phases, than did normal animals. Conclusions: Imbalance in the descending 5-HT pathway in the spinal cord could aggravate the mechanical allodynia and enhance the activation of microglia, suggesting that the spinal 5-HT pathway plays an essential role in maintaining the nociceptive processing in balance between facilitation and inhibition in inflammatory pain caused by carrageenan inflammation.

• The Journal of Korean Academy of Orthopedic Manual Physical Therapy
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• v.29 no.3
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• pp.73-84
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• 2023

Background: This study aimed to compare pressure pain thresholds (PPTs) in the vertebral segments between patients with chronic lower back pain (CLBP) and healthy participants without back pain and to determine the correlation between vertebral bone-segment PPT and pain level, lower back pain dysfunction, and psychological status in patients with CLBP. Methods: The subjects of this study were 23 healthy adults and 23 adults with CLBP. PPT was measured in 23 spinal bone segments using a PPT device, and the CLBP group was subjected to a pain level test (NRS) and a psychological test using the Korean version of the pain catastrophizing scale (KPCS). The functional level was assessed using the Korean version of the Oswestry disability index (KODI). Results: PPTs of the spinal sclerotomes were significantly lower in patients with CLBP than in healthy participants. In the CLBP group, the composite score of lumbar PPTs showed a high correlation with the composite scores for all segments, but not with the pain level (NRS), KPCS score, and spinal sclerotome PPT. Moreover, PPT in the sacral sclerotomes showed a significant negative correlation coefficient with function, with a KODI score of -.462 (p<.01). Conclusion: In this study, PPTs in all spinal segments in patients with CLBP was significantly lower than that in healthy subjects. The PPTs of the lumbar region was significantly correlated with the PPTs of other spinal regions. Through this study, it was found that there were changes in PPTs in CLBP patients not only in the lumbar region but also in other spinal regions. This information should be considered during clinical treatment of patients with low back pain.

• The Korean Journal of Pain
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• v.37 no.2
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• pp.141-150
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• 2024

Background: Stingless bee propolis is a popular traditional folk medicine and has been employed since ancient times. This study aimed to evaluate the antinociceptive activities of the chemical constituents of aqueous propolis extract (APE) collected by Trigona thoracica in a nociceptive model in mice. Methods: The identification of chemical constituents of APE was performed using high-performance liquid chromatography (HPLC). Ninety-six male Swiss mice were administered APE (400 mg/kg, 1,000 mg/kg, and 2,000 mg/kg) before developing nociceptive pain models. Then, the antinociceptive properties of each APE dose were evaluated in acetic acid-induced abdominal constriction, hot plate test, and formalin-induced paw licking test. Administration of normal saline, acetylsalicylic acid (ASA, 100 mg/kg, orally), and morphine (5 mg/kg, intraperitoneally) were used for the experiments. Results: HPLC revealed that the APE from Trigona thoracica contained p-coumaric acid (R² = 0.999) and caffeic acid (R² = 0.998). Although all APE dosages showed inhibition of acetic acid-induced abdominal constriction, only 2,000 mg/kg was comparable to the result of ASA (68.7% vs. 73.3%, respectively). In the hot plate test, only 2,000 mg/kg of APE increased the latency time significantly compared to the control. In the formalin test, the durations of paw licking were significantly reduced at early and late phases in all APE groups with a decrease from 45.1% to 53.3%. Conclusions: APE from Trigona thoracica, containing p-coumaric acid and caffeic acid, exhibited antinociceptive effects, which supports its potential use in targeting the prevention or reversal of central and peripheral sensitization that may produce clinical pain conditions.

• Journal of Oriental Neuropsychiatry
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• v.16 no.2
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• pp.13-24
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• 2005

Background and Objectives : Acupuncture as a therapeutic intervention is widely used for the treatment of many functional disorders such as substance abuse and mental dysfunction. Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug addiction. Yet, there are still many unanswered questions about the basic mechanism of acupuncture. Studies have shown that both the psychomotor stimulant effects and rewarding properties of addictive drugs, including morphine, are sensitized by repeated drug administration and raised the possibility that both of these effects may be linked to the same or closely overlapping the mesolimbic dopamine systems. Neiguan (PC6) point on the pericardium channel which is associated with the brain and its mental function, has been used to treat mental, psychosomatic disorders and gastroenterological disorders. The present study was designed to investigate the effect of acupuncture on repeated morphine-induced changes in extracellular dopamine levels using in vivo microdialysis and to measure the effect of acupuncture on Fos-like immunoreactivity. Methods : Male Sprague-Dawley rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with morphine hydrochloride (5 mg/kg, s.c.). Acupuncture was applied at bilateral Neiguan (PC6) points for 1 min after the morphine challenge. Results showed that acupuncture at the specific acupoint PC6, but not at control points (tail and HE8) significantly decreased Fos-like immunoreactivity induced by a systemic morphine challenge or a single s.c. morphine injection in the morphine-repeated animals. Results and Conclusions : These results suggest that reduction in sensitization may be one mechanism whereby acupuncture alleviates morphine craving in addicts. Moreover, in a more general sense these results suggest that acupuncture can be used as a therapeutic intervention for correcting reversible malfunction of the body by direction of brain pathway and thus acupuncture can contribute to the biochemical balance in the central nervous system by regulating neurotransmitters.

• The Korean Journal of Pain
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• v.13 no.2
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• pp.164-174
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• 2000

Background: After an injury to tissue such as the skin, hyperalgesia develops. Hyperalgesia is characterized by an increase in the magnitude of pain evoked by noxious stimuli. It has been postulated that in the mechanism of hyperalgesia (especially secondary hyperalgesia) and allodynia, a sensitization of central nervous system such as spinal dorsal horn may contribute to development of hyperalgesia. However, the precise mechanism is still unclear. In the present study, we investigated the roles of N-methyl-D-aspartate (NMDA) receptor and nitric oxide (NO) system in the mechanism of hyperalgesia, and their relations with c-fos expression Methods: Inflammation was induced by injection of complete Freund adjuvant (CFA) into unilateral hindpaw of Sprague-Dawley rat. Behavioral studies measuring paw withdrawal responses by von Frey filaments and paw withdrawal latencies by radiant heat stimuli and stainings of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and c-fos immunoreactivity were performed. The effects of MK-801, an NMDA receptor blocker and $N^\omega$-nitro-L-arginine (L-NNA), a nitric oxide synthase (NOS) inhibitor were evaluated. Results: 1) Injection of CFA induced mechanical allodynia, mechanical hyperalgesia and thermal hyperalgesia. And it increased the number of NADPH-diaphorase positive neurons and c-fos expression neurons. 2) MK-801 inhibited mechanical hyperalgesia and thermal hyperalgesia induced by CFA and reduced the number of NADPH-diaphorase positive neurons and c-fos expression neurons. 3) L-NNA inhibited the thermal hyperalgesia and reduced the number of NADPH-diaphorase positive neurons, but did not affect the number of c-fos expression neurons. Conclusions: These results suggest that in the mechanism of mechanical hyperalgesia, NMDA receptor but not NO-system is involved and in the case of thermal hyperalgesia both NMDA receptor and NO system are involved. NO system did not affect the expression of c-fos, but c-fos expression and NOS activity were dependent on the activity of NMDA receptor.

• The Korean Journal of Pain
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• v.30 no.1
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• pp.3-17
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• 2017

Background: Postherpetic neuralgia (PHN) is a common and painful complication of acute herpes zoster. In some cases, it is refractory to medical treatment. Preventing its occurrence is an important issue. We hypothesized that applying nerve blocks during the acute phase of herpes zoster could reduce PHN incidence by attenuating central sensitization and minimizing nerve damage and the anti-inflammatory effects of local anesthetics and steroids. Methods: This systematic review and meta-analysis evaluates the efficacy of using nerve blocks to prevent PHN. We searched the MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov and KoreaMed databases without language restrictions on April, 30 2014. We included all randomized controlled trials performed within 3 weeks after the onset of herpes zoster in order to compare nerve blocks vs active placebo and standard therapy. Results: Nine trials were included in this systematic review and meta-analysis. Nerve blocks reduced the duration of herpes zoster-related pain and PHN incidence of at 3, 6, and 12 months after final intervention. Stellate ganglion block and single epidural injection did not achieve positive outcomes, but administering paravertebral blockage and continuous/repeated epidural blocks reduced PHN incidence at 3 months. None of the included trials reported clinically meaningful serious adverse events. Conclusions: Applying nerve blocks during the acute phase of the herpes zoster shortens the duration of zoster-related pain, and somatic blocks (including paravertebral and repeated/continuous epidural blocks) are recommended to prevent PHN. In future studies, consensus-based PHN definitions, clinical cutoff points that define successful treatment outcomes and standardized outcome-assessment tools will be needed.

• The Korean Journal of Physiology
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• v.23 no.1
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• pp.151-167
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• 1989

The present study was undertaken to investigate modification in electrophysiological characteristics of cat dorsal horn cells resulting from carrageenin-induced inflammation. The followings were studied; 1) the time-course of changes in responses of the WDR (wide dynamic range) cell 1-3h after subcutaneous injection of carrageenin in its receptive field; 2) the responses of the same dorsal hern cells before and after induction of inflammation; 3) the effect of inflammation on the responsiveness of dorsal horn neurons to algogens (bradykinin & potassium); and 4) the effect of inflammation on the activity of WDR cell following administration of indomethacin and clonidine. Though responses of WDR neuron were increased dramatically during first 1h, the maximal enhancement was observed 3h after induction of inflammation especially by repetitive light tactile stimulus. Following carrageenin injection the majority of WDR neurons (10/15 units) showed enhanced responses to all the mechanical stimuli while in 3 cases responsiveness were intensified during activation by one tactile stimulus (brush or pressure). One cell was unaffected by inflammation and in another case the response was enhanced only to noxious stimulus. Five of 9 cells that could initially be driven by noxious stimulus were activated more strongly by same stimulus and even by tactile stimulus (pressure) following inflammation. In 2 cases neurons were sensitized only to noxious stimulus whereas in another 2 cells that did not show enhanced responses to noxious stimulus responses to light tactile stimulus (pressure) appeared after inflammation. Of 16 LT cells tested 6 responded to squeeze while 4 showed the characteristics of WDR cell following inflammation. No modification in responsiveness was recognized in 3 cells whereas response to only brush was enhanced in another 3 neurons. Following carrageenin injection responses of LT cell to bradykinin or $K^{+}$ were not altered whereas those of WOR neurons to bradykinin or $K^{+}$ were suppressed in 22.2% and 33.3% of cases, respectively. In two of 8 activity of HT cells were inhibited by bradykinin while in five of 8 responsiveness to $K^{+}$ were rather enhanced by inflammation. In the rest inflammation was ineffective. In inflammation-induced animal the receptive field of LT cell was not changed whereas those of WDR cell and HT cell were tremendously expanded. The enhanced responses of WDR neurons to mechanical stimuli resulted from inflammation were suppressed by intravenously injected indomethacin and clonidine suggesting that postaglandin is involved in inflammation-induced sensitization of these cells. The involvement of peripheral and central mechanisms in the modification in responsiveness of dorsal horn cells in the carrageenin-induced inflammation was discussed.

• The Journal of Korean Medicine
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• v.26 no.3 s.63
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• pp.1-12
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• 2005

Objectives : Substantial evidence suggests that reinforcing effects of nicotine can be mediated by the mesolimbic dopaminergic system. It has been shown that repeated injections of nicotine produce an increase in locomotor activity and expression of the immediate-early gene, c-fos, in the dopaminergic target areas. Herbal medicine as a therapeutic intervention has been widely used for the treatment of mental dysfunction. Many studies have shown that Radix Scutellariae (RS) can affect the biochemical balance in the central nervous system. Tn order to investigate whether RS has an influence on nicotine-induced behavioral sensitization, we examined the effect of RS on nicotine-induced locomotor activity and c-fos expression in the striatum and nucleus accumbens utilizing the fos-tike immunohistochemistry (FLI). Methods : Male SD rats received RS (200mg/kg, i.p.) 30min before repeated daily injections of nicotine (0.4mg/kg, s.c.) for 7 days. This was followed by withdrawal for 3 days and one challenge for 1 day. Results : System challenge with nicotine produced a much larger increase in locomotor activity and accumbal FLI. Pretreatment with RS significantly inhibited nicotine-induced locomotor activity and FLI in the striatum and nucleus accumbens. Conclusions : These results demonstrate that reduction in locomotor activity by RS may be reflected by reduction of dopamine release and postsynaptic neuronal activity in the striatum and nucleus accumbens. Our results suggest that RS may have therapeutic effect on nicotine addiction.