• The Korean Journal of Pain
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• v.20 no.1
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• pp.21-25
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• 2007

Background: Intrathecal sildenafil has produced antinociception by increasing the cGMP through inhibition of phosphodiesterase 5. Spinal opioid receptor has been reported to be involved in the modulation of nociceptive transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. Methods: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. Results: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. Conclusions: Sildenafil is active against the nociceptive state that's evoked by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level.

• Journal of Dairy Science and Biotechnology
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• v.24 no.2
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• pp.21-24
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• 2006

The ubiquitous presence of lactoferrin(LF) receptor in human as reported by the research group of Prof. Bo Lonnerdal, Univ. California (Suzuki, Y. A.,2001) encouraged us to search for the unknown physiological roles of Lf. Under the collaboration with Prof. Etsumori Harada, Tottori Univ., and his research group, we have found two novel biological activities of LF as the control of the lipid metabolism and the effect on the central nervous system. Relating to the lipid metabolism, LF could, in animal experiments, reduce triglyceride and total cholesterol both in blood and liver (Takeuchi, T et αl., 2003). LF increased plasms HDL-C and lowered LDL-C. In the central nervous system, LF showed anti-nociceptive activity mediated by ${\mu}$-opioid receptor in the rat spinal cord (Hayashida, K. et al., 2003). LF enhanced analgesic action of morphine synergistically via nitric oxide synthesis (Hayashida, K., et al., 2003) LF showed opioid-mediated suppressive effect on distress induced by maternal separation in rat pups (Takeuchi, T., et al., 2003).

• Korean Journal of Plant Resources
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• v.20 no.3
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• pp.221-225
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• 2007

The plant Ligularia fischeri var. spiciformis (Compositae) is a candidate for available functional foods. It has been used to treat diabetes mellitus and rheumatoid arthritis. We have reported the isolation of a new eremophilanolide named 6-oxoeremophilenolide and cytotoxic intermedeol together with the isolation of hydrophilic constituents, chlorogenic acid, 3,4-di-O-caffeoylquinic acie (3), and 5-O-[1-butyl]-3,4-di-O-caffeoylquinic acid. Compound 3 was again isolated by combination of silica gel- and ODS column chromatography for the anti-nociceptive action. Compound 3 and 4 were assayed in hot plate- and writhing tests in the rat. Although the three derivatives of caffeic acid exhibited significant anti-nociceptive effects at 10 mg/kg dose (i.p.),(activity potency: 4>3). These results suggest that compound 3 is responsible for at least rheumatoid arthritis, and caffeic acid moiety is the active moiety of dicaffeoylquinic acid.

• The Korean Journal of Pain
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• v.29 no.3
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• pp.153-157
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• 2016

Tapentadol is a novel oral analgesic with a dual mode of action as an agonist of the ${\mu}$-opioid receptor (MOR), and as a norepinephrine reuptake inhibitor (NRI) all in a single molecule. Immediate release (IR) tapentadol shows its analgesic effect quickly, at around 30 minutes. Its MOR agonistic action produces acute nociceptive pain relief; its role as an NRI brings about chronic neuropathic pain relief. Absorption is rapid, with a mean maximal serum concentration at 1.25-1.5 h after oral intake. It is present primarily in the form of conjugated metabolites after glucuronidation, and excretes rapidly and completely via the kidneys. The most common adverse reactions are nausea, dizziness, vomiting, and somnolence. Constipation is more common in use of the ER formulation. Precautions against concomitant use of central nervous system depressants, including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, or use of tapentadol within 14 days of the cessation of monoamine oxidase inhibitors, are advised. The safety and efficacy have not been established for use during pregnancy, labor, and delivery, or for nursing mothers, pediatric patients less than 18 years of age, and cases of severe renal impairment and severe hepatic impairment. The major concerns for tapentadol are abuse, addiction, seeking behavior, withdrawal, and physical dependence. The presumed problem for use of tapentadol is to control the ratio of MOR agonist and NRI. In conclusion, tapentadol produces both nociceptive and neuropathic pain relief, but with worries about abuse and dependence.

• Biomolecules & Therapeutics
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• v.5 no.2
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• pp.211-214
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• 1997

In the present study, we investigated the mechanisms of antinociceptive effect and thermoregulatory action of capsaicin in guinea pigs. The administration of capsaicin (5 mg/kg, s.c.) caused a significant decrease in frequency of eye wiping, an indicative of nociceptive threshold. This antinociceptive effect of calsaicin was abolished by co-administration of capsazepine (30 mg/kg, s.c.) with capsaicin, suggesting the involvement of a vanilloid receptor in the antinociceptive action of capsaicin. The administration of capsaicin (1 mg/kg, s.c.) produced a significant decrease in body temperature of guinea pigs. The maximum decrease in body temperature by 2 degrees was shown 1 hour after the treatment, and this decrease was not reversed by coadministration of capsazepine. In conclusion, it is suggested that the mechanism of action of capsaicin-induced thermoregulation involves different pathways from that of capsaicin-induced antinociception.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.6
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• pp.687-693
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• 1998

This study was performed to examine the mean arterial pressure and nociceptive jaw opening reflex after microinjection of glutamate into the amygdala in freely moving rats, and to investigate the mechanisms of antinociceptive action of amygdala. Animals were anesthetized with pentobarbital sodium (40 mg/kg, ip). A stainless steel guide cannula (26 gauge) was implanted in the amygdala and lateral ventricle. Stimulating and recording electrodes were implanted into each of the incisor pulp and anterior digastric muscle. Electrodes were led subcutaneously to the miniature cranial connector sealed on the top of the skull with acrylic resin. After 48 hours of recovery from surgery, mean arterial pressure and digastric electromyogram (dEMG) were monitored in freely moving rats. Electrical shocks (200 ${\mu}sec$ duration, $0.5{\sim}2$ mA intensity) were delivered at 0.5 Hz to the dental pulp every 2 minutes. After injection of 0.35 M glutamate into the amygdala, mean arterial pressure was increased by $8{\pm}2$ mmHg and dEMG was suppressed to $71{\pm}5%$ of the control. Injection of 0.7 M glutamate elevated mean arterial pressure by $25{\pm}5$ mmHg and suppressed dEMG to $20{\pm}7%$ of the control. The suppression of dEMG were maintained for 30 minutes. Naloxone, an opioid receptor antagonist, inhibited the suppression of dEMG elicited by amygdaloid injection of glutamate from $28{\pm}4\;to\;68{\pm}5%$ of the control. Methysergide, a serotonin receptor antagonist, also inhibited the suppression of dEMG from $33{\pm}5\;to\;79{\pm}4%$ of the control. However, phentolamine, an ${\alpha}-adrenergic$ receptor antagonist, did not affect the suppression of dEMG. These results suggest that the amygdala can modulate both cardiovascular and nociceptive responses and that the antinociception of amygdala seems to be attributed to an augmentation of descending inhibitory influences on nociceptive pathways via serotonergic and opioid pathways.

• 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 Physiology and Pharmacology
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• v.25 no.4
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• pp.365-374
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• 2021

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 μl) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.

• The Korean Journal of Pain
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• v.27 no.2
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• pp.103-111
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• 2014

Nefopam (NFP) is a non-opioid, non-steroidal, centrally acting analgesic drug that is derivative of the nonsedative benzoxazocine, developed and known in 1960s as fenazocine. Although the mechanisms of analgesic action of NFP are not well understood, they are similar to those of triple neurotransmitter (serotonin, norepinephrine, and dopamine) reuptake inhibitors and anticonvulsants. It has been used mainly as an analgesic drug for nociceptive pain, as well as a treatment for the prevention of postoperative shivering and hiccups. Based on NFP's mechanisms of analgesic action, it is more suitable for the treatment of neuropathic pain. Intravenous administration of NFP should be given in single doses of 20 mg slowly over 15-20 min or with continuous infusion of 60-120 mg/d to minimize adverse effects, such as nausea, cold sweating, dizziness, tachycardia, or drowsiness. The usual dose of oral administration is three to six times per day totaling 90-180 mg. The ceiling effect of its analgesia is uncertain depending on the mechanism of pain relief. In conclusion, the recently discovered dual analgesic mechanisms of action, namely, a) descending pain modulation by triple neurotransmitter reuptake inhibition similar to antidepressants, and b) inhibition of long-term potentiation mediated by NMDA from the inhibition of calcium influx like gabapentinoid anticonvulsants or blockade of voltage-sensitive sodium channels like carbamazepine, enable NFP to be used as a therapeutic agent to treat neuropathic pain.

• The Korean Journal of Pain
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• v.18 no.2
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• pp.113-117
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• 2005

Background: Serotonin 3 receptor is involved in the modulation of nociceptive transmission in the spinal cord. The serotonin 3 receptor antagonist has been used for the management of opioid-induced nausea and vomiting. The aim of this study was to examine whether the analgesic effect of morphine is antagonized by serotonin 3 receptor antagonists at the spinal level. Methods: Rats were implanted with lumbar intrathecal catheters. For nociception, a formalin solution (5%, $50{\mu}l$) was injected into the hind paw of male Sprague-Dawley rats. To determine whether the effect of intrathecal morphine was mediated via serotonin 3 receptors, serotonin 3 receptor antagonists were intrathecally administered 10 min prior to the morphine delivery. Following the formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Results: Intrathecal morphine produced a dose-dependent suppression of the flinches in both phases during the formalin test. The analgesic action of morphine was not reversed by serotonin 3 receptor antagonists (LY-278,584, ondansetron), which had little per se effect on the formalin-induced nociception. Conclusions: Spinal serotonin 3 receptors may not be involved in the analgesia of morphine on a nociceptive state evoked by a formalin stimulus.