• Advances in Traditional Medicine
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• v.6 no.3
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• pp.186-195
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• 2006

The present study was carried out to determine the involvement of opioid and non-opioid receptor and the effect of pH and enzymes on the recently reported antinociceptive activity of aqueous extract of Corchorus olitorius (AECO) leaves using the abdominal constriction test. The extract was prepared by soaking the dried powdered leaves of Corchorus (C.) olitorius in distilled water overnight, and the supernatant obtained was considered as a stock solution with 100% concentration/ strength. The extract, administered subcutaneously in the concentrations/ strength of 10, 50 and 100%, was found to show a significant concentration-independent antinociception. The 50% concentration AECO were further used to study on the above mentioned parameters. The extract exhibited: significant (P < 0.05) decreased in activity when pre-treated (s.c.) against 10 mg/kg naloxonazine, bicuculine (10 mg/kg), phenoxybenzamine (10 mg/kg), 10 mg/kg pindolol, and 5 mg/kg mecamylamme, but not 10 mg/kg naltrindole, 10 mg/kg atropine, respectively; significant (P < 0.05) decreased in activity after pre-treatment against 10% a-amylase, but not 1 % protease or 10% lipase and; significant (P < 0.05) decreased in activity after exposure to alkaline condition (pH between 9 and 13) while maintaining the activity at acidic condition, respectively. The C. olitorius leaves antinociception, which involved, at least in part, activation of $\mu-opioid,\;\alpha-and\;\beta-adrenergic$, and nicotinic receptors, was found to decrease under alkaline condition and in the presence of $\alpha-amylase$.

• The Korean Journal of Pharmacology
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• v.24 no.2
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• pp.153-164
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• 1988

The potential role of endogenous opioid peptides (EOPS) in cardiovascular regulation has only recently been entertained. EOPS have been localized in brain, spinal cord, autonomic ganglia, particularly the adrenal gland, and many other peripheral tissues. There are at least five major types of opioid receptors; namely ${\mu},\;{\delta},\;k,\;{\sigma},\;and\;{\varepsilon}$ and Experimental evidence indicates that cardiovascular actions of the peptide are mediated primarily by ${\mu},\;{\delta}$ and k receptors, and that these receptor types may be allosterically coupled. In anesthetized rabbits met-enkephalin decreased blood pressure and heart rate, which closely paralleled a reduction in sympathetic discharge. Naloxone, but not naloxone methobromide, antagonized these effects, which suggests a central site of action of met-enkephalin. A number of autonomic agents, particularly adrenergic ${\alpha}$-and, ${\beta}-agonists$ and antagonists modify the cardiovascular actions of met-enkephalin. Experiments in reserpine-treated and adrenalectomized rats provide no evidence of sympathetic nervous system involvement in the pressor responses to intravenous injection of opioid peptides, but rather suggest a direct peripheral action. Finally, activation of a beta-endorphinergic pathway projecting from the arcuate nucleus to the nucleus tractos solitarii in rats can cause naloxone reversible hypotension and bradycardia. There is evidence to implicate this pathway in antihypertensive drug action and in the modulation of baroreflex activity.

• The Korean Journal of Pain
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• v.32 no.2
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• pp.79-86
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• 2019

Background: The use of aroma oils dates back to at least 3000 B.C., where it was applied to mummify corpses and treat the wounds of soldiers. Since the 1920s, the term "aromatherapy" has been used for fragrance therapy with essential oils. The purpose of this study was to determine whether the essential oil of Eucalyptus (EOE) affects pain pathways in various pain conditions and motor coordination. Methods: Mice were subjected to inhalation or intraperitoneal injection of EOE, and its analgesic effects were assessed by conducting formalin, thermal plantar, and acetic acid tests; the effects of EOE on motor coordination were evaluated using a rotarod test. To determine the analgesic mechanism, 5'-guanidinonaltrindole (${\kappa}$-opioid antagonist, 0.3 mg/kg), naltrindole (${\delta}$-opioid antagonist, 5 mg/kg), glibenclamide (${\delta}$-opioid antagonist, 2 mg/kg), and naloxone (${\mu}$-opioid antagonist, 4, 8, 12 mg/kg) were injected intraperitoneally. Results: EOE showed an analgesic effect against visceral pain caused by acetic acid (EOE, 45 mg/kg); however, no analgesic effect was observed against thermal nociceptive pain. Moreover, it was demonstrated that EOE did not have an effect on motor coordination. In addition, an anti-inflammatory effect was observed during the formalin test. Conclusions: EOE, which is associated with the ${\mu}$-opioid pain pathway, showed potential effects against somatic, inflammatory, and visceral pain and could be a potential therapeutic agent for pain.

• The Korean Journal of Pain
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• v.35 no.4
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• pp.433-439
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• 2022

Background: Repeated administration of opioid analgesics for pain treatment can produce paradoxical hyperalgesia via peripheral and/or central mechanisms. Thus, this study investigated whether spinally (centrally) administered orexin A attenuates opioid-induced hyperalgesia (OIH). Methods: [D-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin (DAMGO), a selective µ-opioid receptor agonist, was used to induce mechanical hypersensitivity and was administered intradermally (4 times, 1-hour intervals) on the rat hind paw dorsum. To determine whether post- or pretreatments with spinal orexin A, dynorphin A, and anti-dynorphin A were effective in OIH, the drugs were injected through an intrathecal catheter whose tip was positioned dorsally at the L3 segment of the spinal cord (5 ㎍ for all). Mechanical hypersensitivity was assessed using von Frey monofilaments. Results: Repeated intradermal injections of DAMGO resulted in mechanical hypersensitivity in rats, lasting more than 8 days. Although the first intrathecal treatment of orexin A on the 6th day after DAMGO exposure did not show any significant effect on the mechanical threshold, the second (on the 8th day) significantly attenuated the DAMGO-induced mechanical hypersensitivity, which disappeared when the type 1 orexin receptor (OX1R) was blocked. However, intrathecal administration of dynorphin or an anti-dynorphin antibody (dynorphin antagonists) had no effect on DAMGO-induced hypersensitivity. Lastly, pretreatment with orexin A, dynorphin, or anti-dynorphin did not prevent DAMGO-induced mechanical hypersensitivity. Conclusions: Spinal orexin A attenuates mechanical hyperalgesia induced by repetitive intradermal injections of DAMGO through OX1R. These data suggest that OIH can be potentially treated by activating the orexin A-OX1R pathway in the spinal dorsal horn.

• The Korean Journal of Pain
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• v.14 no.2
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• pp.150-155
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• 2001

Background: Tramadol is known to be a weak opioid. However, it has also been shown that tramadol is an effective norepinephrine and serotonin uptake blocker, which may be effective in the treatment of neuropathic pain. The present study was undertaken in order to assess the antinociceptive action of tramadol and to investigate possible antinociceptive mechanisms by using antagonists in an animal neuropathic pain models in rats. Methods: Rats were prepared with tight ligation at the left 5 and 6th lumbar spinal nerves (Kim and Chung's neuropathic pain model). The antinociceptive effects of tramadol (10, 20, and 50 mg/kg i.p.) in rats with neuropathic pain were assessed. Additionally, following coadministration of antagonists such as naloxone (1 mg/kg i.p.), yohimbine (1 mg/kg i.p.) and ritanserin (1 mg/kg i.p.) with 50 mg/kg of tramadol, the responses to mechanical and thermal stimuli were measured over a two-hour period. Results: Tramadol displayed potent antinociceptive effects in a dose-dependent manner on rats with neuropathic pain (P < 0.05). The effects of tramadol were inhibited by coadministered naloxone and yohimbine in rats with mechanical and thermal allodynia, respectively (P < 0.05). However, there were no significant changes in the pain behaviors in the case of ritanserin. Conclusions: Tramadol showed significant antinociceptive effects in rats with regards to neuropathic pain against both mechanical and thermal allodynia. The antinociceptive effect on the mechanical stimuli is medicated via an opioid receptor. However, it appears that the antinociceptive effects on thermal allodynia are mediated via a noradrenalin receptor vice a serotonergic receptor.

• The Journal of Korean Medicine
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• v.26 no.3 s.63
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• pp.239-248
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• 2005

Objectives : Electroacupuncture (EA)-induced analgesia has been known to be mediated through the activation of opioid, noradrenergic and serotonergic receptors. However, little study on serotonergic mechanism has been performed in an animal model of chronic pain. The present study was designed to elucidate the type of serotonergic receptors responsible for EA analgesia in the chronic pain model. Methods : In rats with complete Freund's: adjuvant-induced inflammation and spinal nerve injury, spinal wide dynamic range (WDR) cell responses to graded electrical stimulation of afferent C fiber were recorded before and after spinal application of selective 5-hydroxytryptamine (5-HT) receptor antagonists. EA stimulation (2Hz, 0.5msec, 3mA) was applied to the contralateral Zusanli point for 30 min. Results : In both models of chronic pain, WDR cell responses were greatly inhibited after EA stimulation. EA-induced inhibition of WDR celt responses was significantly attenuated by spinal application of non-selective 5-HT receptor antagonist, dihydroergocristine Of 5-HT receptor antagonists tested, 5-HT1A (WAY 100635) and 5-HT2 (LY53857) receptor antagonists strongly reduced an ability of EA stimulation to inhibit WDR cell responses. However, 5-HT1B (GR55562) and 5-HT3 (LY278584) receptor antagonists also had weak but significant blocking action on EA-induced inhibitory effect on chronic pain. Conclusions : Dorsal hem cell responses, afferent C fiber stimulation, chronic pain, electroacupuncture, serotonergic receptors.

• The Korean Journal of Pain
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• v.23 no.2
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• pp.99-108
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• 2010

Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel ${\alpha}2-{\delta}$ ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment.

• Korean Journal of Biological Psychiatry
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• v.5 no.1
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• pp.34-45
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• 1998

We provide the reader with a brief introduction to the neurobiology of neuropeptides. Several comprehensive reviews of the distribution and neurochemical, neurophysiological, neuropharmacological and behavioral effects of the major neuropeptides have recently appeared. In reviews of the large number of neuropeptides in brain and their occurance in brain regions thought to be involved in the pathogenesis of major psychiatric disorders, investigators have sought to determine whether alternations in neuropeptide systems are associated with schizophrenia, mood disorders, anxiety disorders, alcoholism and neurodegenerative disease. There is no longer any doubt that neuropeptide-containing neurons are altered in several neuropsychiatric disorders. One of the factors that has hindered neuropeptide research to a considerable extent is the lack of pharmacological agents that specifically alter the synaptic availability of neuropeptides. With the exception of naloxone and naltrexone, the opiate-receptor antagonists, there are few available neuropeptide- receptor antagonists. Two independent classes of neuropeptide-receptor antagonists has been expected to be clinically useful. Naltrexone, a potent ${\mu}$-receptor antagonist, has been used successfully to reduce the need for alcohol consumption. And cholecycstokinin antagonists are now in development as a new class of anxiolytics, which would be expected to be free from tolerance and physical dependence and lack of sedation. In this review, we deal with these two kinds of neuropeptide system, the opioid system and cholesystokinins in the brain. The role of opioid systems in the reinforcement after alcohol consumtion and that of cholesystokinins in the pathogenesis of anxiety will be discussed briefly. As we know, the future for neuropeptides in psychiatry remains bright indeed.

• The Korean Journal of Pain
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• v.37 no.1
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• pp.26-33
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• 2024

Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Methods: Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K_ATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Results: Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT₂) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions: NO/cGMP/K_ATP, 5HT₃ and D₂ pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.

• 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.