• The Korean Journal of Pain
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• v.18 no.2
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• pp.133-137
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• 2005

Background: Cannabinoids have shown antinociceptive action. The aims of this study were to examine the effect of chronic infusion of a cannabinoids receptors agonist (WIN 55,212-2) for thermal nociception at the spinal level, and to also observe the development of toxicity. Methods: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters with the nociceptive response (withdrawal response latency) determined by exposing the plantar surface of the hindpaw to radiant heat. Initially, the effect of intrathecal WIN 55,212-2 was evaluated followed by the change in the effect at 1, 2, 3 and 4 weeks after repeated infusion. Finally, the histopathological findings were assessed 1 and 4 weeks following the infusion of WIN 55,212-2. Results: Intrathecal WIN 55,212-2 was found to produce a limited antinociception during the thermal test. %MPE of WIN 55,212-2 at 1, 2, 3, and 4 weeks after infusion was not different from each other. No abnormal pathological findings were observed following a chronic intrathecal infusion of WIN 55,212-2. Conclusions: WIN 55,212-2, a cannabinoids receptors agonist, may be useful in the management of thermal nociception, without changing the effectiveness or causing the toxicity following a chronic infusion at the spinal level.

• The Korean Journal of Physiology
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• v.23 no.1
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• pp.139-149
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• 1989

Although tail flick reflex (TFR) in rats has been used as a classic model of the nociceptive test to evaluate the action of analgesics, there have been few studies on the origin of the latent period of TFR. Present study was performed to elucidate the mechanism of increase in latency of TFR by morphine in anesthetized rats. Tail skin and dorsolateral tail nerve were stimulated electrically and EMG activities were recorded from abductor caudae dorsalis muscle participating in tail flick reflex. In the case of noxious radiant heat stimulation to tail, the tail flick tension was recorded before and after administration of morphine. Then changes in latency and conduction velocity of peripheral nerve were evaluated. The results obtained were as follows: 1) The latencies of TFR evoked by the electrical stimulation of tail skin and dorsolateral tail nerve were all within 40 ms and were elongated by several milliseconds from control after the administration of morphine. Peripheral conduction velocities of tail flick afferent nerve were within the range of 10-25 m/s. 2) The conduction velocity of peripheral nerve was significantly reduced after morphine administration, therefore the afferent time (utilization time+conduction time to spinal cord) was significantly increased. But the time for central delay and efferent time was not affected by morphine. 3) The conduction velocity under room temperature $(20-25^{\circ}C)$ was significantly reduced after morphine while that under vasodilation state $(40{\sim}42^{\circ}C)$ increased, 30 min and 45 min after morphine. The conduction velocity under vasodilation state without treatment of morphine increased continuously 4) The latency in tension response of TFR evoked by electrical stimulation was elongated by several milliseconds from control while the latency evoked by noxious radiant heat was elongated by several seconds compared with that of control. From the above results, it could be concluded that: 1) the increased latency of TFR evoked by electrical stimulation of the tail after morphine administration was due to the reducton in conduction velocity of peripheral nerve, which was the secondry effect of morphine on the peripheral vasomotion and 2) increased latency of TFR evoked by noxious radiant heat was also due to the same effect of morphine and the increase in cutaneous insulation to the noxious heat.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.18 no.4
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• pp.679-700
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• 1996

Inferior alveolar nerve dysfunction may be the result of trauma, disease, or iatrogenic injury. Inferior alveolar nerve injury is inherent risk in endodontic therapy, orthognathic surgery of the mandible, and extraction of mandibular teeth, particularly the third molars. The sensory disturbances of inferior alveolar nerve associated with such injury have been well documented clinical problem that is commonly evaluated by several clinical sensory test including Tinels sign, Von Frey test(static light touch detection), directional discrimination, two-point discrimination, pin pressure nociceptive discrimination, and thermal test. These methods used to detect and assess inferior alveolar nerve injury have been subjective in nature, relying on the cooperation of the patients. In addition, many of these techniques are sensitive to differences in the examiners experience and skill with the particular technique. Data obtained at different times or by different examiners are therefore difficult to compare. Prior experimental studies have used electro diagnostic methods(sensory evoked potential) to objectively evaluate inferior alveolar nerve after nerve injury. This study was designed with inferior alveolar nerve of rabbit. Several types of injury including mind, moderate, severe compression and perforation with 19 gauze, 21 gauze needle and 6mm, 10mm traction were applied for taking the sesory evoked ppterntial. Latency and amplitude of injury rabbit inferior alveolar nerve were investigated with sensory evoked potential using unpaired t-test. The results were as follows : 1. Intensity of threshold (T1) was $128{\pm}16{\mu}A$ : latency, $0.87{\pm}0.07$ microsecond : amplitude, $0.4{\pm}0.1{\mu}V$ : conduction velocity, 23.3 m/s in sensory evoked potential of uninjured rabbit inferior alveolar nerve. 2. Rabbit inferior alveolar nerve consists of type II and III sensory nerve fiber. 3. Latency was increased and amplitude was decreased in compression injury. The more injured, the more changed in latency and amplitude. 4. Findings in perforation injury was similar to compression injury. Waveform for sensory evoked potential improved by increasing postinjured time. 5. Increasing latency was prominent in traction injury rabbit inferior alveolar nerve. 6. In microscopic histopathological findings, significant degeneration and disorganization of the internal architecture were seen in nerve facicle of severe compression and 10mm traction group. From the above findings, electrophysiological assessment(sensory evoked potential) of rabbit injured inferior alveolar nerve is reliable technique in diagnosis and prognosis of nerve injury.

• The Korean Journal of Pain
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• v.22 no.1
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• pp.16-20
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• 2009

Background: Zaprinast is an inhibitor of phosphodiesterase 5, 6 and 9. Phosphodiesterase inhibitors could produce anti-nociceptive effects by promoting the accumulation of cGMP. We hypothesized that intrathecal zaprinast could attenuate the allodynia induced by chronic constriction injury of the sciatic nerve in rat. Methods: Sprague-Dawley rats were prepared with four loose ligations of the left sciatic nerve just proximal to the trifurcation into the sural, peroneal and tibial nerve branches. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. The thresholds for the withdrawal responses were assessed. Zaprinast ($3-100{\mu}g$) was administered intrathecally by the direct lumbar puncture method to obtain the dose-response curve and the 50% effective dose ($ED_{50}$). Measurements were taken before and 15, 30, 45, 60, 90, 120, and 180 min after the intrathecal doses of zaprinast. The side effects were also observed. Results: Intrathecal zaprinast resulted in a dose-dependent antiallodynic effect. The maximal effects occurred within 15-30 min and then they gradually decreased down to the baseline level over time in all the groups. There was a dose dependent increase in the magnitude and duration of the effect. The $ED_{50}$ value was $17.4{\mu}g$ (95% confidence intervals; $14.7-20.5{\mu}g$). No severe motor weakness or sedation was observed in any of the rats. Conclusions: Intrathecally administered zaprinast produced a dose-dependent antiallodynic effect in the chronic constriction injury neuropathic pain model. These findings suggest that spinal phosphodiesterase 5, 6 and 9 may play an important role in the modulation of neuropathic pain.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.5
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• pp.539-546
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• 2018

Botulinum toxin type A (BoNT/A) has been used therapeutically for various conditions including dystonia, cerebral palsy, wrinkle, hyperhidrosis and pain control. The substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) receive orofacial nociceptive information from primary afferents and transmit the information to higher brain center. Although many studies have shown the analgesic effects of BoNT/A, the effects of BoNT/A at the central nervous system and the action mechanism are not well understood. Therefore, the effects of BoNT/A on the spontaneous postsynaptic currents (sPSCs) in the SG neurons were investigated. In whole cell voltage clamp mode, the frequency of sPSCs was increased in 18 (37.5%) neurons, decreased in 5 (10.4%) neurons and not affected in 25 (52.1%) of 48 neurons tested by BoNT/A (3 nM). Similar proportions of frequency variation of sPSCs were observed in 1 and 10 nM BoNT/A and no significant differences were observed in the relative mean frequencies of sPSCs among 1-10 nM BoNT/A. BoNT/A-induced frequency increase of sPSCs was not affected by pretreated tetrodotoxin ($0.5{\mu}M$). In addition, the frequency of sIPSCs in the presence of CNQX ($10{\mu}M$) and AP5 ($20{\mu}M$) was increased in 10 (53%) neurons, decreased in 1 (5%) neuron and not affected in 8 (42%) of 19 neurons tested by BoNT/A (3 nM). These results demonstrate that BoNT/A increases the frequency of sIPSCs on SG neurons of the Vc at least partly and can provide an evidence for rapid action of BoNT/A at the central nervous system.

• Korean Journal of Plant Resources
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• v.28 no.5
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• pp.591-599
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• 2015

Osteoarthritis (OA) is a degenerative disease characterized by the progressive degradation of joint cartilage and is accompanied by secondary inflammation of synovial membranes. The purpose of this study describes a preliminary evaluation of the anti-inflammatory activity on test material of Litsea japonica. fruit (LJTM) Also, this study was to evaluate the effects of LJTM on the joint cartilage of rat with OA induced by monosodium iodoacetate (MIA). To study for anti-inflammatory agents effectively, we first examined the inhibitory effect of the LJTM on the production of pro-inflammatory factors and cytokines stimulated with lipopolysaccharide. We identified anti-nociceptive effects of the LJTM by using in vivo peripheral and central nervous pain models. In addition, the aim of this study was to evaluate the effects on mRNA expression of MMP-2, -3, -7, -9, -13, TIMP-1 and –2 in cartilage of OA. In the LJTM inhibited production of pro-inflammatory mediators (NO and PGE₂) and pro-inflammatory cytokines (TNF-α and IL-6). In cartilage, Expression of MMPs and TIMPs mRNA was suppressed in LJTM treatment group than in the control group. This study suggests that LJTM are potential candidates as anti-inflammation and anti-osteoarthritis agents (painkillers) for the treatment of OA.

• Restorative Dentistry and Endodontics
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• v.32 no.6
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• pp.514-521
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• 2007

The purinoreceptor, $P2X_3$ is a ligand-gated cation channel activated by extracellular ATP. It has been reported that ATP can be released during inflammation and tissue damage, which in turn may activate $P2X_3$ receptors to initiate nociceptive signals. However, little is known about the contribution of $P2X_3$ to the dental pain during pulpal inflammation. Therefore, the purpose of this study was to investigate the expression of $P2X_3$ and its colocalization with TRPV1 to understand the mechanism of pain transmission through $P2X_3$ in the human dental pulp with double labeling immunofluorescence method. In the human dental pulp, intense $P2X_3$ immunoreactiyity was observed throughout the coronal and radicular pulp. Of all $P2X_3$-positive fibers examined, 79.4% coexpressed TRPV1. This result suggests that $P2X_3$ along with TRPV1 may be involved in the transmission of pain and potentiation of noxious stimuli during pulpal inflammation.

• Journal of Physiology & Pathology in Korean Medicine
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• v.29 no.1
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• pp.18-26
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• 2015

Akebiae Caulis is a galenical originated from Akebia quinata Decaisne species. It is commonly used in the treatment of oposiuria, inflammation, nociceptive and fever. Here, we investigated the effect of Akebiae Caulis extract (ACE) to protect hepatocyte against the malfunction of mitochondria and apoptosis. Arachidonic acid (AA)+iron promoted excessive reactive oxygen species (ROS) production and exerted a deleterious effect on mitochondria. Treatment with ACE protected hepatocytes from AA+iron-induced cytotoxicity, as shown by alterations in the protein levels related with apoptosis such as poly(ADP-ribose) polymerase, pro-caspase 3, Bcl-XL and Bcl-2. Moreover, AA+iron-induced $H_2O_2$ production, GSH depletion and mitochondrial dysfunction were alleviated by ACE pretreatment. As a potential molecular mechanism for the ACE-mediated cytoprotection, phosphorylation of AMP-activated protein kinase (AMPK), a key regulator in determining cell survival or death, was increased by ACE. Moreover, ACE treatment enhanced inactive phosphorylation of glycogen synthase kinase-$3{\beta}$ ($GSK3{\beta}$), downstream substrate kinase of AMPK. More importantly, ACE prevented a decrease in the $GSK3{\beta}$ phosphorylation derived by AA+iron, which might contribute to mitohondiral protection and cell survival. To further identify essential compounds in Akebiae Caulis for the protection of AA+iron-mediated cytotoxicity, we found that betulin in combination with hederagenin protected from AA+iron-induced mitochondrial dysfunction. Betulin+hederagenin treatment also increased inactive phosphorylation of $GSK3{\beta}$ in common with ACE. These results suggest that ACE protected hepatocytes against oxidative stress and mitochondrial dysfunction, which is mediated with inactive $GSK3{\beta}$ phosphorylation downstream of AMPK.

• Journal of Neurogastroenterology and Motility
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• v.24 no.4
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• pp.656-668
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• 2018

Background/Aims MicroRNAs (miRNAs) were reported to be responsible for intestinal permeability in diarrhea-predominant irritable bowel syndrome (IBS-D) rats in our previous study. However, whether and how miRNAs regulate visceral hypersensitivity in IBS-D remains largely unknown. Methods We established the IBS-D rat model and evaluated it using the nociceptive visceral hypersensitivity test, myeloperoxidase activity assay, restraint stress-induced defecation, and electromyographic (EMG) activity. The distal colon was subjected to miRNA microarray analysis followed by isolation and culture of colonic epithelial cells (CECs). Bioinformatic analysis and further experiments, including dual luciferase assays, quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay, were used to detect the expression of miRNAs and how it regulates visceral hypersensitivity in IBS-D rats. Results The IBS-D rat model was successfully established. A total of 24 miRNAs were differentially expressed in the distal colon of IBS-D rats; 9 were upregulated and 15 were downregulated. Among them, the most significant upregulation was miR-200a, accompanied by downregulation of cannabinoid receptor 1 (CNR1) and serotonin transporter (SERT). MiR-200a mimic markedly inhibited the expression of CNR1/SERT. Bioinformatic analysis and luciferase assay confirmed that CNR1/SERT are direct targets of miR-200a. Rescue experiments that overexpressed CNR1/SERT significantly abolished the inhibitory effect of miR-200a on the IBS-D rats CECs. Conclusions This study suggests that miR-200a could induce visceral hyperalgesia by targeting the downregulation of CNR1 and SERT, aggravating or leading to the development and progression of IBS-D. MiR-200a may be a regulator of visceral hypersensitivity, which provides potential targets for the treatment of IBS-D.

• Korean Journal of Psychosomatic Medicine
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• v.28 no.2
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• pp.99-107
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• 2020

Fibromyalgia is a disorder characterized by the core symptom of chronic widespread pain, along with fatigue, sleep disturbances, mood changes, and cognitive difficulties. The etiology of fibromyalgia involves a combination of biological factors, such as genetic vulnerability, alterations in pain processing and stress response system ; psychological factors, such as anxiety, depression, anger, and perceived stress ; environmental factors, such as infections, febrile diseases, and trauma. Central sensitization, which is amplified in the process of sensory stimulation, has been emphasized as a key etiological factor, as supported by enhanced wind-up, delayed aftersensation, decreased nociceptive flexion reflex threshold and functional imaging studies. Several guidelines recommend that a multimodal approach be used to treat fibromyalgia, including both pharmacological and non-pharmacological treatments, tailored to each individual, and that clinicians should provide an intellectual framework through sufficient education and emphasis on the importance of self-management. The prevalence of mood disorders, anxiety disorders, and other psychiatric problems is 7-9 times higher in patients with fibromyalgia than in the general population ; moreover, the association between fibromyalgia and certain psychopathologies or sleep problems has also been suggested. Since psychiatric problems, with shared vulnerabilities and risk factors, interact with fibromyalgia bidirectionally and also affect the disease course, an integrated management approach is needed to determine the risk of comorbidities.