• Journal of Acupuncture Research
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• v.18 no.6
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• pp.215-224
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• 2001

Objcetive : Neuropathic pain sometimes arises from a partial peripheral nerve injury. This kind of pain is usually accompanied by spontaneous burning pain, allodynia and hyperalgesia. It has been well known that acupuncture is effective to the pain control from ancient time in Asia. However, it is not clear whether acupuncture can control neuropathic pain. The aim of the present study is to examine if acupuncture stimulation may be effective to the mechanical allodynia in a rat model of neuropathic pain. Methods : To produce neuropathic pain, under sodium pentobarbital anesthesia, the right superior caudal trunk was resected between the S3 and S4 spinal nerves. After the neuropathic surgery, we examined if the animals exhibited the behavioral signs of mechanical allodynia. The mechanical allodynia was assessed by stimulating the tail with von Frey hair (bending force : 2.0g). three or 6 weeks after the neuropathic surgery, acupuncture stimulation was delivered to Houxi (SI 3) as the following parameters (2HZ frequency, 0.07mA intensity and 3msec duration) for 30 minutes. Results : The stimulation of Houxi (SI 3) acupoint relieved the behavioral signs of mechanical allodynia. Conclusion : Our results suggest that acupuncture can control the mechanical allodynia of neuropathic pain.

• The Korean Journal of Pain
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• v.34 no.3
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• pp.262-270
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• 2021

Background: Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel implicated in pain sensation in response to heat, protons, and capsaicin (CAPS). It is well established that TRPV1 is involved in mechanical allodynia. This study investigates the effect of Ononis spinosa (Fabaceae) in CAPS-induced mechanical allodynia and its mechanism of action. Methods: Mechanical allodynia was induced by the intraplantar (ipl) injection of 40 ㎍ CAPS into the left hind paw of male Wistar rats. Animals received an ipl injection of 100 ㎍ O. spinosa methanolic leaf extract or 2.5% diclofenac sodium 20 minutes before CAPS injection. Paw withdrawal threshold (PWT) was measured using von Frey filament 30, 90, and 150 minutes after CAPS injection. A molecular docking tool, AutoDock 4.2, was used to study the binding energies and intermolecular interactions between O. spinosa constituents and TRPV1 receptor. Results: The ipsilateral ipl injection of O. spinosa before CAPS injection increased PWT in rats at all time points. O. spinosa decreased mechanical allodynia by 5.35-fold compared to a 3.59-fold decrease produced by diclofenac sodium. The ipsilateral pretreatment with TRPV1 antagonist (300 ㎍ 4-[3-Chloro-2-pyridinyl]-N-[4-[1,1-dimethylethyl] phenyl]-1-piperazinecarboxamide [BCTC]) as well as the β2-adrenoreceptor antagonist (150 ㎍ butoxamine) attenuated the action of O. spinosa. Depending on molecular docking results, the activity of the extract could be attributed to the bindings of campesterol, stigmasterol, and ononin compounds to TRPV1. Conclusions: O. spinosa alleviated CAPS-induced mechanical allodynia through 2 mechanisms: the direct modulation of TRPV1 and the involvement of β2 adrenoreceptor signaling.

• The Korean Journal of Pain
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• v.34 no.2
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• pp.165-175
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• 2021

Background: Management of pain from open wounds is a growing unmet healthcare need. However, the models available to study pain from wounds or to develop analgesics for the patients suffering from them have primarily relied on incisional models. Here, we present the first characterized and validated model of open wound pain. Methods: Unilateral full-skin excisional punch biopsy wounds on rat hind paws were evaluated for evoked pain using withdrawal responses to mechanical and thermal stimulation, and spontaneous pain was measured using hind paw weight distribution and guarding behavior. Evaluations were done before wounding (baseline) and 2-96 hours post-wounding. The model was validated by testing the effects of buprenorphine and carprofen. Results: Pain responses to all tests increased within 2 hours post-wounding and were sustained for at least 4 days. Buprenorphine caused a reversal of all four pain responses at 1 and 4 hours post-treatment compared to 0.9% saline (P < 0.001). Carprofen decreased the pain response to thermal stimulation at 1 (P ≤ 0.049) and 4 hours (P < 0.011) post-treatment compared to 0.9% saline, but not to mechanical stimulation. Conclusions: This is the first well-characterized and validated model of pain from open wounds and will allow study of the pathophysiology of pain in open wounds and the development of wound-specific analgesics.

• The Korean Journal of Pain
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• v.19 no.1
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• pp.33-44
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• 2006

Background: Peripheral nerve injury leads to neuropathic pain, including mechanical hyperalgesia (MH). Nerve discharges produced by an injury to the primary afferents cause the release of glutamate from both central and peripheral terminals. While the role of centrally released glutamate in MH has been well studied, relatively little is known about its peripheral role. This study was carried out to determine if the peripherally conducting nerve impulses and peripheral glutamate receptors contribute to the generation of neuropathic pain. Methods: Rats that had previously received a left L5 dorsal rhizotomy were subjected to a spinal nerve lesion (SNL) or brief electrical stimulation (ES, 4 Hz pulses for 5 min) of the left L5 spinal nerve. The paw withdrawal threshold (PWT) to von Frey filaments was measured. The effects of an intraplantar (i.pl.) injection of a glutamate receptor (GluR) antagonist or agonist on the changes in the SNL- or ES-produced PWT was investigated. Results: SNL produced MH, as evidenced by decrease in the PWT, which lasted for more than 42 days. ES also produced MH lasting for 7 days. MK-801 (NMDAR antagonist), DL-AP3 (group-I mGluR antagonist), and APDC (group-II mGluR agonist) delayed the onset of MH when an i.pl. injection was given before SNL. The same application blocked the onset of ES-induced MH. NBQX (AMPA receptor antagonist) had no effect on either the SNL- or ES-induced onset of MH. When drugs were given after SNL or ES, MK-801 reversed the MH, whereas NBQX, DL-AP3, and APDC had no effect. Conclusions: Peripherally conducting impulses play an important role in the generation of neuropathic pain, which is mediated by the peripheral glutamate receptors.

• Journal of Korean Neurosurgical Society
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• v.52 no.1
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• pp.32-36
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• 2012

Objective : Alcoholic neuropathy is characterized by allodynia (a discomfort evoked by normally innocuous stimuli), hyperalgesia (an exaggerated pain in response to painful stimuli) and spontaneous burning pain. The aim of the present study is to investigate the effect of rolipram, a phosphodiesterase 4 inhibitor, against alcohol-induced neuropathy in rats. Methods : Allodynia was induced by administering 35% v/v ethanol (10 g/kg; oral gavage) to Spraue-Dawley rats for 8 weeks. Rolipram and saline (vehicle) were administered intraperitoneally. Mechanical allodynia was measured by using von Frey filaments. Somatosensory evoked potential (SEP) was proposed as complementary measure to assess the integrity of nerve pathway. Results : The ethanol-induced mechanical allodynia began to manifest from 3 week, and then peaked within 1 week. Beginning from 3 week, latency significantly started to increased in control group. In rolipram treated rats, the shorter latency was sustained until 8 weeks (p<0.05). The mechanical allodynia, which began to manifest on the 3 weeks, intraperitoneal injections of rolipram sustained statistical difference until 8 weeks, the final week of the study (p<0.05). Conclusion : This study suggests that rolipram might alleviate mechanical allodynia induced by alcohol in rats, which clearly has clinical implication.

• The Korean Journal of Pain
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• v.13 no.1
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• pp.19-30
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• 2000

Background: Partial nerve injury to a peripheral nerve may induce the development of neuropathic pain which is characterized by symptoms such as spontaneous burning pain, allodynia and hyperalgesia. Though underlying mechanism has not fully understood, sensitization of dorsal horn neurons may contribute to generate such symptoms. Nitric oxide acts as an inter- and intracellular messenger in the nervous system and is produced from L-arginine by nitric oxide synthase (NOS). Evidence is accumulating which indicate that nitric oxide may mediate nociceptive information transmission. Recently, it has been reported that NOS inhibitor suppresses neuropathic pain behavior in an neuropathic pain animal model. This study was conducted to determine whether nitric oxide could be involved in the sensitization of dorsal horn neurons in neuropathic animal model. Methods: Neuropathic animal model was made by tightly ligating the left L5 and L6 spinal nerves and we examined the effects of iontophoretically applied NOS inhibitor (L-NAME) on the dorsal horn neuron's responses to mechanical stimuli within the receptive fields. Results: In normal animals, NOS inhibitor (L-NAME) specifically suppressed the responses to the noxious mechanical stimuli. In neuropathic animals, the dorsal horn neuron's responses to mechanical stimuli were enhanced and NOS inhibitor suppressed the dorsal horn neuron's enhanced responses to non-noxious stimuli as well as those to noxious ones. Conclusions: These results suggest that nitric oxide may mediate nociceptive transmission in normal animal and also mediate sensitization of dorsal horn neurons in neuropathic pain state.

• The Korean Journal of Pain
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• v.25 no.4
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• pp.213-220
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• 2012

Background: It has been demonstrated that the expression of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and apoptotic cell death in the dorsal root ganglion (DRG) following spinal nerve constriction injury play a role in the initiation and continuation of hyperalgesia and allodynia. The present study was designed to investigate the effects of ethyl pyruvate (EP) on mechanical and cold allodynia, TNF-${\alpha}$ expression, and apoptosis in DRG after spinal nerve ligation injury. Methods: Rats were divided into 3 groups: control, pre-EP, and post-EP. EP (50 mg/kg) was intraperitoneally injected 30 minutes before (pre-EP) or after (post-EP) surgery. Behavioral tests to determine mechanical and cold allodynia were conducted before surgery and 4 and 7 days after surgery. Seven days after surgery, TNF-${\alpha}$ protein levels in DRG were evaluated by enzyme-linked immunosorbent assay, and DRG apoptosis was determined by immunohistochemical detection of activated caspase-3. Results: Treatment with EP significantly reduced mechanical and cold allodynia following spinal nerve ligation injury. TNF-${\alpha}$ protein levels in the pre-EP ($4.7{\pm}1.2$ pg/200 ${\mu}g$; P < 0.001) and post-EP ($6.4{\pm}1.8$ pg/200 ${\mu}g$; P < 0.001) groups were 2-3 times lower than the control group ($14.4{\pm}1.2$ pg/200 ${\mu}g$). The percentages of neurons and satellite cells that co-localized with caspase-3 were also significantly lower in the pre-EP and post-EP groups than the control group. Conclusions: These results demonstrate that EP has a strong anti-allodynic effect that acts through the inhibition of TNF-${\alpha}$ expression and apoptosis in DRG after spinal nerve ligation injury.

• Journal of Physiology & Pathology in Korean Medicine
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• v.32 no.1
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• pp.35-42
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• 2018

TRPA1 and TRPV1 are members of the TRP superfamily of structurally related, nonselective cation channels. TRPA1 and TRPV1 are often co-expressed in sensory neurons and play an important role in mechanical hyperalgesia and allodynia during neuropathic pain. Scutellariae Radix was reported to possess anti-inflammation properties and similar patterns of therapeutic action against different diseases. also Baicalin(a known principal constituent of Scutellaria Radix) was shown to down-regulate the mRNA expression levels of TRPV1. In this study, we observed the effects of Scutellariae Radix extract(SRE) in neuropathic pain induced SD rats via modulation of TRPV1 and TRPA1. Oral administration of a Scutellaria Radix extract(in doses of 300mg/kg, SRE(300)) showed a meaningful increase in the withdrawal threshold of mechanical allodynia and showed a meaningful decrease in the expression of c-fos compared to the control group. SRE(100) and SRE(300) showed a meaningful decrease in the expression of TRPV1 level compared to the control group. These results suggest that Scutellariae Radix extract could decrease mechanical allodynia by down-regulate the TRPV1 on the model of neuropathic pain.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.5
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• pp.255-261
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• 2006

Melittin-induced nociceptive responses are mediated by selective activation of capsaicin-sensitive primary afferent fibers and are modulated by excitatory amino acid receptor, cyclooxygenase, protein kinase C and serotonin receptor. The present study was undertaken to investigate the peripheral and spinal actions of voltage-gated calcium channel antagonists on melittin-induced nociceptive responses. Changes in mechanical threshold and number of flinchings were measured after intraplantar (i.pl.) injection of melittin $(30\;{\mu}g/paw)$ into mid-plantar area of hindpaw. L-type calcium channel antagonists, verapamil [intrathecal (i.t.), 6 or $12\;{\mu}g$; i.pl.,100 & $200\;{\mu}g$; i.p., 10 or 30 mg], N-type calcium channel blocker, ${\omega}-conotoxin$ GVIA (i.t., 0.1 or $0.5\;{\mu}g$; i.pl., $5\;{\mu}g$) and P-type calcium channel antagonist, ${\omega}-agatoxin$ IVA (i.t., $0.5\;{\mu}g$; i.pl., $5\;{\mu}g$) were administered 20 min before or 60 min after i.pl. injection of melittin. Intraplantar pre-treatment and i.t. pre- or post-treatment of verapamil and ${\omega}-conotoxin$ GVIA dose-dependently attenuated the reduction of mechanical threshold, and melittin-induced flinchings were inhibited by i.pl. or i.t. pre-treatment of both antagonists. P-type calcium channel blocker, ${\omega}-agatoxin$ IVA, had significant inhibitory action on flinching behaviors, but had a limited effect on melittin-induced decrease in mechanical threshold. These experimental findings suggest that verapamil and ${\omega}-conotoxin$ GVIA can inhibit the development and maintenance of melittin-induced nociceptive responses.

• The Korean Journal of Pain
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• v.34 no.4
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• pp.394-404
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• 2021

Background: We aimed to investigate the effect of epidural polydeoxyribonucleotide (PDRN) on mechanical allodynia and motor dysfunction in a rat model of lumbar foraminal stenosis (LFS). Methods: This study was conducted in two stages, using male Sprague-Dawley rats. The rats were randomly divided into eight groups. In the first stage, the groups were as follows: vehicle (V), sham (S), and epidural PDRN at 5 (P5), 8 (P8), and 10 (P10) mg/kg; and in the second stage, they were as follows: intraperitoneal PDRN 8 mg/kg, epidural 3,7-dimethyl-1-propargilxanthine (DMPX) (0.1 mg/kg), and DMPX (0.1 mg/kg). The LFS model was established, except for the S group. After an epidural injection of the test solutions, von Frey and treadmill tests were conducted for 3 weeks. Subsequently, histopathologic examinations were conducted in the V, S, P5, and P10 groups. Results: A total of 65 rats were included. The P8 and P10 groups showed significant recovery from mechanical allodynia and motor dysfunction at all time points after drug administration compared to the V group. These effects were abolished by concomitant administration of DMPX. On histopathological examination, no epineurial inflammation or fibrosis was observed in the epidural PDRN groups. Conclusions: Epidural injection of PDRN significantly improves mechanical allodynia and motor dysfunction in a rat model of LFS, which is mediated by the spinal adenosine A_2A receptor. The present data support the need for further research to determine the role of epidural PDRN in spinal stenosis treatment.