• The Korean Journal of Pain
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• v.35 no.3
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• pp.261-270
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• 2022

Background: The rostral ventromedial medulla (RVM) is a critical region for the management of nociception. The RVM is also involved in learning and memory processes due to its relationship with the hippocampus. The purpose of the present study was to investigate the molecular mechanisms behind orexin-A signaling in the RVM and hippocampus's effects on capsaicin-induced pulpal nociception and cognitive impairments in rats. Methods: Capsaicin (100 g) was applied intradentally to male Wistar rats to induce inflammatory pulpal nociception. Orexin-A and an orexin-1 receptor antagonist (SB-334867) were then microinjected into the RVM. Immunoblotting and immunofluorescence staining were used to check the levels of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) in the RVM and hippocampus. Results: Interdental capsaicin treatment resulted in nociceptive responses as well as a reduction in spatial learning and memory. Additionally, it resulted in decreased BDNF and increased COX-2 expression levels. Orexin-A administration (50 pmol/1 µL/rat) could reverse such molecular changes. SB-334867 microinjection (80 nM/1 µL/rat) suppressed orexin's effects. Conclusions: Orexin-A signaling in the RVM and hippocampus modulates capsaicin-induced pulpal nociception in male rats by increasing BDNF expression and decreasing COX-2 expression.

• Natural Product Sciences
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• v.20 no.4
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• pp.285-289
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• 2014

Pyrrosia lingua has been widely used as a traditional medicine for the treatment of lots of diseases including pain management. However pharmacological and phytochemical studies on its anti-nociceptive properties are extremely limited. In this work, we investigated the effects of methanol extract of Pyrrosia lingua (MPL, 250 and 500 mg/kg) on the both of central and peripheral nociceptive pain. The results from tail-immersion test and hotplate test revealed that MPL has potent anti-nociceptive effects on thermal nociception. In addition, MPL efficiently reduced the acetic acid-induced chemical nociception compared to indomethacin. We also carried out formalin test and MPL reduced formalin-induced pain response on both phases, suggesting MPL has antinociceptive activities on the central and peripheral pain. In combination test using naloxone, anti-nocicpetive activity of MPL was reduced, indicating that MPL acts as a partial opioid receptor agonist. These results suggest that MPL may be possibly used as a valuable natural product-derived painkiller.

• Biomolecules & Therapeutics
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• v.24 no.4
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• pp.418-425
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• 2016

We measured anti-nociceptive activity of prim-o-glucosylcimifugin (POG), a molecule from Saposhnikovia divaricate (Turcz) Schischk. Anti-nociceptive or anti-inflammatory effects of POG on a formalin-induced tonic nociceptive response and a complete Freund's adjuvant (CFA) inoculation-induced rat arthritis pain model were studied. Single subcutaneous injections of POG produced potent anti-nociception in both models that was comparable to indomethacin analgesia. Anti-nociceptive activity of POG was dose-dependent, maximally reducing pain 56.6% with an $ED_{50}$ of 1.6 mg. Rats given POG over time did not develop tolerance. POG also time-dependently reduced serum TNF${\alpha}$, IL-$1{\beta}$ and IL-6 in arthritic rats and both POG and indomethacin reduced spinal prostaglandin E2 ($PGE_2$). Like indomethacin which inhibits cyclooxygenase-2 (COX-2) activity, POG dose-dependently decreased spinal COX-2 content in arthritic rats. Additionally, POG, and its metabolite cimifugin, downregulated COX-2 expression in vitro. Thus, POG produced potent anti-nociception by downregulating spinal COX-2 expression.

• Natural Product Sciences
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• v.20 no.4
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• pp.301-305
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• 2014

The aim of our study is to investigate the anti-nociceptive and anti-inflammatory properties of an ethanol extract of the leaf and stem of Aralia cordata. Writhing responses induced by acetic acid, tail immersion test, and formalin-induced paw pain response for nociception and formalin-induced paw edema for inflammation were evaluated in mice. A. cordata (50 - 200 mg/kg, p.o.) and ibuprofen (100 mg/kg, p.o.), a positive non-steroidal anti-inflammatory drugs (NSAIDs), inhibited the acetic acid-induced writhing response, but they did not protect the thermal nociception in tail immersion test. However, morphine (5 mg/kg, s.c.) used as positive opioid control alleviated both the acetic acid-induced writhing response and thermal nociception in tail immersion test. In the formalin test, A. cordata (50 - 200mg/kg) and ibuprofen (200mg/kg) inhibited the second phase response (peripheral inflammatory response), but not the first phase response (central response), whereas morphine inhibited both phase pain responses. Both A. cordata (100 mg/kg) and ibuprofen (200 mg/kg) significantly alleviated the formalin-induced increase of paw thickness, the index of inflammation. These results show for the first time that the leaf and stem of A. cordata has a significant anti-nociceptive effect that seems to be peripheral, but not central. A. cordata also displays an anti-inflammatory activity in an acute inflammation model. The present study supports a possible use of the leaf and stem of A. cordata to treat pain and inflammation.

• Natural Product Sciences
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• v.19 no.4
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• pp.311-315
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• 2013

Ribes fasciculatum (Saxifragaceae) has been widely used as a traditional medicine for the treatment of cough, antidote, cold, lacquer poison, and sore throat. In the present study, we evaluated the anti-nociceptive effects of ethyl acetate fraction of Ribes fasciculatum (ERF) in mice. Test results of tail-immersion test and hot plate test revealed that the ERF had strong anti-nociceptive activities on thermal nociception in a dose dependent manner, indicating ERF's anti-nociception on the central pain. Moreover, the acetic acid-induced chemical nociception was also significantly reduced by ERF treatment. This result shows that ERF may also work on the peripheral pain. We further performed formalin test to confirm ERF's anti-nociceptive properties and found that pain responses were significantly decreased by ERF treatment. Interestingly, in the combination test with naloxone, the analgesic activity of ERF was not changed, indicating that the opioid receptor was not involved in the ERF-mediated anti-nociception. These results indicate that ERF might be possibly used as a painkiller for the treatment of nociceptive pains.

• Korean Journal of Pharmacognosy
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• v.44 no.1
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• pp.70-74
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• 2013

Ligularia stenocephala has been widely used as a traditional medicine for the treatment of lots of diseases such as asthma, arthritis, and jaundice. In this study, we evaluated the anti-nocicepitve activities of methanolic extract of L. stenocephala (MLS) using various pain models including thermal nociception as well as chemical nociception methods. MLS showed significant increase in latency time in the tail immersion test and hot-plate test. In addition, the number of acetic acid-induced abdominal constrictions was decreased by MLS. MLS also attenuated paw licking time in the formalin test. The combination test using naloxone revealed that the anti-nociceptive properties of MLS was not associated with opioid receptor activation. The present results demonstrate that MLS may possibly used as valuable analgesic agent for the treatment of nociceptive pain.

• Korean Journal of Pharmacognosy
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• v.44 no.2
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• pp.188-192
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• 2013

Acer tegmentosum which is belongs to Aceraceae has been widely used as a traditional medicine for the treatment of lots of diseases including pain management. In this study, we evaluated the anti-nocicepitve effects of methanolic extract of A. tegmentosum (MAT) in mice using various pain models. MAT presented strong and dose-dependent anti-nociceptive activities on thermal nociception models such as tail-immersion test and hot plate test. Moreover, acetic acid-induced chemical nociception was signigicantly reduced by MAT treatment. We could confirm MAT's central and peripheral analgesic properties by formalin test. We also found that the pre-treatment of opioid receptor antagonist did not alter the MAT's anti-nociception, suggesting opioid receptor is not involved in analgesic activity of MAT. Based on our results, we could conclude that MAT may be possibly used as an anti-nociceptive agent for the treatment of various nociceptive pains.

• International Journal of Oral Biology
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• v.32 no.2
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• pp.59-65
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• 2007

It has been well known that excitatory amino acids, primarily glutamate, are involved in the transmission of nociception in pathological and physiological conditions in the spinal and brainstem level. Recently, peripheral glutamate also play a critical role in the peripheral nociceptive transmissions. The present study investigated the role of N-methyl-D-aspartic acid (NMDA) or non-NMDA ionotropic glutamate receptors in formalin-induced TMJ pain. Experiments were carried out on male Sprague-Dawley rats weighing 220-280 g. Intra-articular injection was performed under halothane anesthesia. Under anesthesia, AP-7 (10, $100\;{\mu}M$, $1\;mM/20\;{\mu}L$), a NMDA receptor antagonist, or CNQX disodium salt (0.5, 5, 50, $500\;{\mu}M/20\;{\mu}L$), a non-NMDA receptor antagonist, were administered intra-articularly 10 min prior to the application of 5% formalin. For each animal, the number of behavioral responses, such as rubbing and/or scratching the TMJ region, was recorded for nine successive 5-min intervals. Intra-articular pretreatment with 1 mM of AP-7 or $50\;{\mu}M$ CNQX significantly decreased the formalin-induced scratching behavioral responses during the second phase. Intra-articular pretreatment with $500\;{\mu}M$ of CNQX significantly decreased the formalin-induced scratching behavior during both the first and the second phase. These results indicate that the intra-articular administration of NMDA or non-NMDA receptor antagonists inhibit formalin-induced TMJ nociception, and peripheral ionotropic glutamate receptors may play an important role in the TMJ nociception.

• International Journal of Oral Biology
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• v.41 no.3
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• pp.125-131
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• 2016

The aim of the present study was to develop an animal model for evaluation of temporomandibular (TMJ) nociception under TMJ inflammation. We also investigated the participation of $IL-1{\beta}$ in inflammation-induced TMJ nociception. Experiments were carried out using male Sprague-Dawley rats. Intra-articular injection of 3% formalin was administered to evaluate hyperalgesia 3 days after CFA injection. Intra-articular injection of 3% formalin did not produce nociceptive behavior in normal rats. Although intra-articular injection of 3 doses of CFA produced TMJ inflammation, only 1:3 diluted CFA produced hyperalgesia when formalin was injected intra-articularly 3 days after CFA injection. Co-administration of IL-1 receptor inhibitor with formalin into the TMJ cavity 3 days after CFA injection was performed. Co-administration of IL-1 receptor inhibitor significantly inhibited formalin-induced hyperalgesia in rats with CFA-induced TMJ inflammation. These results suggested that intra-articular injection of formalin produced hyperalgesia under chronic TMJ inflammation. Moreover, $IL-1{\beta}$ plays an important role in TMJ hyperalgesia under chronic inflammation and blockade of $IL-1{\beta}$ is a potential therapeutic target for inflammatory TMJ pain.

• Korean Journal of Pharmacognosy
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• v.54 no.2
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• pp.61-65
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• 2023

Clerodendrum trichotomum has been widely used as a traditional medicine for the treatment of numerous diseases, including pain management. However, there have been extremely limited pharmacological and phytochemical studies on Clerodendrum trichotomum up to now. In this study, we investigated the effects of the methanolic extract of Clerodendrum trichotomum (MCT) on nociceptive pain in mice. Our finding demonstrate that MCT treatment significantly extended the latency time in both the tail-immersion test and hot-plate test. Additionally, MCT treatment reduced acetic acid-induced writhing motions. These results suggest that MCT possesses strong anti-nociceptive activities against thermal and chemical nociception. In the formalin test, mice fed with MCT exhibited reduced licking time during both the early and late phases, thereby confirming the therapeutic potential of MCT in central and peripheral nociception. Furthermore, in combination tests using naloxone, the MCT-mediated anti-nociception was slightly reduced, indicating that MCT might act as a partial opioid receptor agonist. Based on these results, MCT may be a valuable candidate for the development of anti-nociceptive agents.