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The influences of temperature and naloxone on the antinociceptive activity of Corchorus olitorius L. in mice

Zakaria ZA, Safarul M, Valsala R, Sulaiman MR, Fatimah CA, Somchit MN, et al.

Naunyn Schmiedebergs Arch Pharmacol, 2005 Jul;372(1):55-62.
PMID: 16133487

A series of preliminary studies was carried out to evaluate the antinociceptive (pain relief) activity of the aqueous extract of Corchorus olitorius L. leaves (COAE) and to determine the influence of temperature and opioid receptors on COAE activity using the abdominal constriction and hot plate tests in mice. COAE, at concentrations of 10, 25, 50, 75, and 100%, showed both peripheral and central antinociception that are non-concentration- and concentration-dependent respectively. The peripheral activity was clearly observed at a concentration of 25% and diminished at a concentration of 100%, while the central activity was observed at all the concentrations of COAE used. Furthermore, the insignificant results obtained indicated that this peripheral activity (at concentrations of 25 and 50%) was comparable to that of morphine (0.8 mg/kg). Pre-heating COAE at a temperature of 80 degrees C and 100 degrees C, or 60 degrees C and 80 degrees C was found to enhance its peripheral and central antinociception respectively. Pre-treatment with naloxone (10 mg/kg), a general opioid receptor antagonist, for 5 min, followed by COAE, was found to completely block its peripheral, but not central, antinociceptive activity. Based on this observation, we conclude that the antinociceptive activity exhibited by C. olitorius is enhanced by the increase in temperature and may be mediated peripherally, but not centrally, at least in part, via an opioid receptor.

Matched MeSH terms: Naloxone/pharmacology*
The effect of endogenous opioids on blood pressure during stress

Nordin M, Morat P, Zainora M

Clin Exp Pharmacol Physiol, 1987 Apr;14(4):303-8.
PMID: 3665195

1. A series of experiments were conducted to investigate the effect of endogenous opioids on blood pressure of laboratory rats during stress. 2. Rats subjected to 120 min immobilization showed a significant drop in systolic pressure which could be prevented by pretreatment injections of naloxone. 3. Adrenalectomized rats subjected to the same kind of stress showed a drop in systolic pressure equivalent to only 30% of the systolic pressure drop in the intact animals. This decrease in systolic pressure could also be prevented by pretreatment injections of naloxone. 4. It was concluded that the decrease in systolic pressure in intact rats during immobilization was mostly due to endogenous opioids released from the adrenal glands, whereas opioids of other origins such as the pituitary gland, were also important.

Matched MeSH terms: Naloxone/pharmacology
Regeneration of adrenal cortical tissue after adrenal autotransplantation

Nabishah BM, Khalid BA, Morat PB, Zanariyah A

Exp. Clin. Endocrinol. Diabetes, 1998;106(5):419-24.
PMID: 9831309

This study tested the possibility of adrenal autotransplantation in rats. Since the cortex and the medulla of the adrenal gland were from different origin embryologically, either whole adrenal glands (ADR), or capsule and cortex (CAP) or medulla (MED) were autotransplanted in the subcutaneous tissue. The functions of regenerated adrenal nodules were tested by measuring plasma corticosterone levels every fortnight. At the end of 9 weeks the rats were exposed to hypovolemic shock followed by naloxone injection to reverse the shock response. Results showed that rats transplanted with either cortex or whole adrenal started secreting corticosterone at 5 weeks post-transplantation (107.73 +/- 21.98 ng/ml, 126.04 +/- 48.41 ng/ml, respectively). Corticosterone levels increased to the value which were not significantly different from control by 9 weeks post-transplantation. However, rats transplanted with adrenal medulla showed very low corticosterone levels. Nine weeks post-transplantation, the mean blood pressure (MBP) of the CAP group was 135 +/- 13 mmHg and was not significantly different from sham-operated controls, whereas MBP of MED group was significantly lower than sham-operated animals (99 +/- 11 mmHg versus 141 +/- 9 mmHg). The MBP of the ADR group was also lower compared to sham-operated controls (112 +/- 17 mmHg P < 0.05). The MBP of the adrenal group was not statistically significant compared to the CAP group. After 1% body weight haemorrhage, the MBP decreased significantly in ADR (45 +/- 5 mmHg, P < 0.05) and MED group (36 +/- 9 mmHg, P < 0.001) compared to sham-operated rats (78 +/- 11 mmHg) but not in the CAP (56 +/- 9 mmHg). It was concluded that autotransplanted whole adrenal or adrenocortical tissues survived subcutaneously and produced sufficient corticosterone to alleviate haemorrhagic shock. Adrenal medullary tissue failed to regenerate subcutaneously and the presence of adrenal medullary tissue may suppressed the growth of transplanted adrenal gland.

Matched MeSH terms: Naloxone/pharmacology
Preliminary analysis of the antinociceptive activity of zerumbone

Sulaiman MR, Perimal EK, Zakaria ZA, Mokhtar F, Akhtar MN, Lajis NH, et al.

Fitoterapia, 2009 Jun;80(4):230-2.
PMID: 19535012 DOI: 10.1016/j.fitote.2009.02.002

We have investigated the antinociceptive activity of zerumbone (1), a natural cyclic sesquiterpene isolated from Zingiber zerumbet Smith, in acetic acid-induced abdominal writhing test and hot plate test in mice. 1 given by intraperitoneal route produced significant dose-dependent antinociceptive effect in all the test models used. In addition, the antinociceptive effect of 1 in the hot plate test was reversed by the non-selective opioid receptor antagonist naloxone, suggesting that the opioid system is involved in its analgesic mechanism of action.

Matched MeSH terms: Naloxone/pharmacology
Fulltext Polymethoxyflavones fromNicotiana plumbaginifolia(Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice

Shajib MS, Rashid RB, Ming LC, Islam S, Sarker MMR, Nahar L, et al.

Front Pharmacol, 2018;9:85.
PMID: 29515437 DOI: 10.3389/fphar.2018.00085

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties.Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone (1), 3,3',4',5',5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4',5'-dimethylenedioxy-3,5,3'-trimethoxyflavone (3), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified fromN. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds1,3, and4(12.5-25 mg/kg b.w.) exhibited dose-dependent and significant (p< 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound1,3, and4(12.5 mg/kg b.w.) demonstrated significant (p< 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAAreceptor in the action of compound3and4was evident from the reversal effects of flumazenil. In addition, compounds1and4(12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1-4) fromN. Plumbaginifoliacould be considered as suitable candidates for the development of analgesic and anxiolytic agents.

Matched MeSH terms: Naloxone
Pentylenetetrazol-like stimulus is not produced following naloxone-precipitated mitragynine withdrawal in rats

Johari IS, Harun N, Sofian ZM, Shoaib M

Psychopharmacology (Berl), 2021 Nov;238(11):3183-3191.
PMID: 34333672 DOI: 10.1007/s00213-021-05934-4

RATIONALE: Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited.
OBJECTIVES: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus.
METHODS: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration.
RESULTS: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points.
CONCLUSION: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder.

Matched MeSH terms: Naloxone/pharmacology
Fulltext Patients that benefit from buprenorphine-naloxone on medically assisted treatment for opioid dependence in Malaysia

George P, Ramasamy P, Thurairajasingam S, Shah Z

Med J Malaysia, 2015 Aug;70(4):251-5.
PMID: 26358024 MyJurnal

INTRODUCTION: Opioid dependence is recorded as the most common drug of abuse in Malaysia. Currently, the preferred substitution therapy for most Government treatment centres is methadone used as substitution therapy for opioid dependence. There are, however patients who may benefit from being on the combined buprenorphine-naloxone formulation as substitution therapy instead. We discuss six cases of opioid dependence of varied backgrounds that were treated with buprenorphinenaloxone therapy and their outcomes.

DISCUSSION: All of the reported patients improved after the induction of buprenorphine- naloxone. Two of the cases highlighted the transfer of patients on methadone to buprenorphine-naloxone due to the adverse effect and interactions of methadone with other medications. During the transfer there were no major adverse reactions noted, and patients were safely able to continue with the maintenance therapy of buprenorphine- naloxone.

CONCLUSION: Buprenorphine-naloxone is a safe and effective drug substitution therapy for opioid dependence. It has fewer interactions with other medications, and has similar efficacy to methadone. Being a partial agonist, it has a less sedating effect making patients more functional.

Matched MeSH terms: Buprenorphine, Naloxone Drug Combination
PKC inhibitor reversed the suppressive effect of orexin-A on IPSCs of locus coeruleus neurons in naloxone-induced morphine withdrawal

Davoudi M, Vijeepallam K, Azizi H, Mirnajafi-Zadeh J, Semnanian S

J Neural Transm (Vienna), 2019 11;126(11):1425-1435.
PMID: 31493096 DOI: 10.1007/s00702-019-02064-2

The locus coeruleus (LC) as a target of addictive drugs receives a dense projection of orexinergic fibres from the lateral hypothalamus (LH) and is accordingly a candidate site for the expression of the somatic aspects of morphine withdrawal. Recently it has been shown that the inhibitory synaptic currents of LC neurons decrease partly through orexin type 1 receptors in the context of naloxone-induced morphine withdrawal; however, its cellular mechanism remains unclear. In this study, whole-cell patch clamp recordings of LC neurons in brainstem slices were used to investigate the impact of protein kinase C (PKC) on GABAergic inhibitory post-synaptic currents (IPSCs) in the context of naloxone-induced morphine withdrawal. Male Wistar rats (P14-P21) received morphine (20 mg/kg, i.p.) daily for 7 consecutive days to induce morphine dependency. Our results showed that the application of PKC inhibitor (Go 6983; 1 µM) alone did not decrease the probability of GABA release in the LC neurons of the morphine-treated rats in the presence of naloxone. Although, Go 6983 reversed the reduction of the amplitude of evoked IPSCs (eIPSCs) and spontaneous IPSCs (sIPSCs) frequency induced by orexin-A but did not change the sIPSCs amplitude. These results indicate that the suppressive effect of orexin-A on IPSCs is probably reversed by PKC inhibitor in the LC neurons of morphine-treated rats in the context of naloxone withdrawal.

Matched MeSH terms: Naloxone/pharmacology*
Outcomes from the Malaysian Arm of The International Survey Informing Greater Insights in Opioid Dependence Treatment (INSIGHT) Project

George P

Med J Malaysia, 2015 Apr;70(2):117-24.
PMID: 26162395 MyJurnal

BACKGROUND: Opioid dependence (OD) is a chronic, relapsing condition representing a significant societal burden in Asia. Opioid maintenance treatment (OMT) in combination with psychosocial treatment is considered to be the most effective strategy to treat opioid dependence. In Malaysia, about 52,000 patients reported receiving OMT in December 2012.
OBJECTIVE: The International Survey Informing Greater Insights in Opioid Dependence Treatment (INSIGHT) project aimed to assess aspects of OMT access and quality of care by surveying patients and users with opioid dependence, and healthcare professionals treating opioid-dependent patients.
MATERIALS AND METHODS: Using a structured questionnaire, 50 patients who were currently receiving OMT (or had received OMT in the past 3 months) and 77 physicians were surveyed in Malaysia regarding the provision and quality of OMT.
RESULTS: Patients were predominately male and in their thirties. Nearly all patients (98%) reported currently receiving methadone liquid; almost half (48%) reported ever having received psychosocial counselling and only 14% had ever received buprenorphine-naloxone in the past. Most physicians reported they were treating their patients with OMT (77% on methadone and 15% on buprenorphine-naloxone), and 3% used psychosocial counselling alone. Although methadone maintenance doses were close to levels recommended by WHO guidelines, induction doses of methadone, and both induction and maintenance doses of buprenorphine were well below these levels in Malaysia.
CONCLUSIONS: The findings suggest that OMT implementation in Malaysia can be improved by providing patients with more education on treatment options, better access to available treatments, including abuse-deterrent formulations, and psychosocial support.

Matched MeSH terms: Buprenorphine, Naloxone Drug Combination
Opioid receptors mediate the acquisition, but not the expression of mitragynine-induced conditioned place preference in rats

Yusoff NHM, Mansor SM, Müller CP, Hassan Z

Behav Brain Res, 2017 08 14;332:1-6.
PMID: 28559179 DOI: 10.1016/j.bbr.2017.05.059

Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0mg/kg) on the acquisition of mitragynine (10mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors.

Matched MeSH terms: Naloxone/pharmacology
Fulltext Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents

Narasingam M, Pandy V, Mohamed Z

Exp Anim, 2016 May 20;65(2):157-64.
PMID: 26744024 DOI: 10.1538/expanim.15-0088

The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal.

Matched MeSH terms: Naloxone
Naloxone and vitamin E block stress-induced reduction of locomotor activity and elevation of plasma corticosterone

Ainsah O, Nabishah BM, Osman CB, Khalid BA

Exp. Clin. Endocrinol. Diabetes, 1999;107(7):462-7.
PMID: 10595599

Normal rats, on being repetitively stressed by being restrained in a tight container for two hours, had higher levels of plasma corticosterone compared to pre stress values. These rats also reacted to the stress by a behavioral response in which there was marked decrease in locomotor activity assessed by the open field test (pre stress: 71.3 +/- 2.6 squares crossed versus post stress: 14.3 +/- 2.5 squares crossed) by counting the number of squares entered by the rat over 5 minutes. By the 6th to 7th exposures to the repetitive stress, the rats adapted to the stress and had normal plasma corticosterone levels and locomotor activity scores comparable to the pre stress values. These responses to stress were completely blocked by the administration of 0.32 microg/100 g BW of naloxone i.p at 10 minutes prior to the stress. In rats fed with rat chow supplemented with 90 mg/kg rat chow or 150 mg/kg rat chow of vitamin E, there was significant reduction of the plasma corticosterone levels and improvement in the locomotor activity. Stress thus caused opioid mediated increase in plasma corticosterone and reduction in locomotor activity which could be blocked by naloxone. These stress responses probably also involved generation of oxygen free radicals which were scavenged by the vitamin E, thus reducing the effects of repetitive stress on locomotor activity and serum corticosterone levels.

Matched MeSH terms: Naloxone/pharmacology*
Mineralocorticoid and glycyrrhizic acid block stress induced hypotension in rats

Ruszymah BH, Nabishah BM, Aminuddin S, Khalid BA

Clin Exp Pharmacol Physiol, 1995 Jan;22(1):35-9.
PMID: 7768032

1. The aim of this study was to investigate the effect of repeated exposure to stress on tail blood pressure (TBP) of normal as well as GCA (glycyrrhizic acid) and steroid treated rats. Male Sprague-Dawley rats (250 g) were exposed to ether vapour to achieve light anaesthesia prior to TBP recording. Rats were injected with either normal saline or naloxone prior to exposure to stress. Tail blood pressure was recorded daily for 2 weeks. 2. We found that ether stress caused a transient drop in TBP in control as well as in dexamethasone (DEX) treated rats. The stress-induced fall in blood pressure was reduced by naloxone in control rats but not in DEX treated rats. However the transient drop in TBP following stress was not seen in either GCA or deoxycorticosterone (DOC) treated rats. 3. We conclude that first, the reduction in TBP was due to the release of endogenous opioids caused by stress. Second, DOC may block the release of such endogenous opioids, preventing the drop in TBP in response to stress, while DEX did not. Third, GCA caused a similar mineralocorticoid effect on reversing stress induced hypotension.

Matched MeSH terms: Naloxone/pharmacology
Fulltext Methanolic Extract of Clinacanthus nutans Exerts Antinociceptive Activity via the Opioid/Nitric Oxide-Mediated, but cGMP-Independent, Pathways

Abdul Rahim MH, Zakaria ZA, Mohd Sani MH, Omar MH, Yakob Y, Cheema MS, et al.

Evid Based Complement Alternat Med, 2016;2016:1494981.
PMID: 27190528 DOI: 10.1155/2016/1494981

The objectives of the present study were to determine the mechanisms of antinociceptive effect of methanol extract of Clinacanthus nutans (Acanthaceae) leaves (MECN) using various animal nociceptive models. The antinociceptive activity of orally administered 10% DMSO, 100 mg/kg acetylsalicylic acid (ASA), 5 mg/kg morphine, or MECN (100, 250, and 500 mg/kg) was determined using the acetic acid-induced abdominal constriction (ACT), formalin-induced paw licking (FT), and hot plate tests (HPT). The role of opioid and nitric oxide/cyclic guanosine monophosphate (NO/cGMP) systems was also investigated. The results showed that MECN produced a significant (p < 0.05) antinociceptive response in all nociceptive models with the recorded ED50 value of 279.3 mg/kg for the ACT, while, for the early and late phases of the FT, the value was >500 mg/kg or 227.7 mg/kg, respectively. This antinociceptive activity was fully antagonized by naloxone (a nonselective opioid antagonist) but was partially reversed by l-arginine (l-arg; a nitric oxide [NO] precursor), Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; an NO synthase inhibitor), or their combinations thereof. In contrast, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor) enhanced the extract's antinociception. UHPLC analysis revealed the presence of several flavonoid-based compounds with antinociceptive action. In conclusion, MECN exerted the peripherally and centrally mediated antinociceptive activity via the modulation of the opioid/NO-mediated, but cGMP-independent, systems.

Matched MeSH terms: Naloxone
Fulltext Lack of reduction in buprenorphine injection after introduction of co-formulated buprenorphine/naloxone to the Malaysian market

Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL

Am J Drug Alcohol Abuse, 2009;35(2):68-72.
PMID: 19212931 DOI: 10.1080/00952990802585406

Diversion of buprenorphine (BPN) has been described in settings where it is legally prescribed and has resulted in increasing concern. To address this concern, co-formulation of buprenorphine/naloxone (BPN/NLX) replaced buprenorphine alone in Malaysia in December 2006.

Matched MeSH terms: Buprenorphine, Naloxone Drug Combination; Naloxone/administration & dosage; Naloxone/adverse effects*
Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia

Vicknasingam B, Mazlan M, Schottenfeld RS, Chawarski MC

Drug Alcohol Depend, 2010 Sep 1;111(1-2):44-9.
PMID: 20478668 DOI: 10.1016/j.drugalcdep.2010.03.014

Buprenorphine maintenance is efficacious for treating opioid dependence, but problems with diversion and misuse of buprenorphine (BUP) may limit its acceptability and dissemination. The buprenorphine/naloxone combination tablet (BNX) was developed to reduce potential problems with diversion and abuse. This paper provides data regarding the characteristics of BUP injection drug users in Malaysia and preliminary data regarding the impact of withdrawing BUP and introducing BNX. BUP was introduced in 2002 and subsequently withdrawn from the Malaysian market in 2006. BNX was introduced in 2007.

Matched MeSH terms: Naloxone/administration & dosage*
Fulltext Inhibitory effects of cardamonin on compound action potentials in frog sciatic nerves and the possible involvement of opioidergic pathway

Sambasevam, Yogesvari, Wong, Siong Jiun, Farihah Hanani Ghazali, Ammar Izzati Amir Ramadan, Mohd Roslan Sulaiman, Mohd Khairi Hussain, et al.

Life Sciences, Medicine and Biomedicine, 2017;1(1):18-24.
MyJurnal

Introduction: Active compounds derived from plants are able to inhibit nerve conduction. Cardamonin, a naturally occurring chalcone, manifests anti-nociceptive, anti-inflammatory and anti-neuropathy properties. Consequently, cardamonin may potentially inhibit nerve action potential, whereby, it affects the nerve conduction. Compound action potential is the sum of the activity which is measured from a nerve trunk. Objective: The experiment was carried out to investigate the inhibitory effect of cardamonin on compound action potentials and its possible mechanism of action on frog sciatic nerve. Methodology: LabTutor software was used to record compound action potentials in frog sciatic nerve. Sciatic nerve was isolated from the frog and soaked in Ringer’s solution. Stimulating electrodes were used to stimulate the nerve and recording electrodes were used to record compound action potentials. Compound action potential of the nerve were recorded before and after treatments [vehicle, cardamonin (0.5, 1 & 2 mg/ml) & morphine (3mg/ml)]. Participation of opioid system was investigated by pre-treating the nerve with naloxone and followed by cardamonin. All the data were recorded and analysed via LabTutor software. The data were analysed by using Two-way ANOVA followed by Bonferonni’s post hoc test with significant value at P < 0.05. Results: The outcomes showed that all the doses of cardamonin significantly reduced the peak amplitude of compound action potential in frog sciatic nerves. Besides, co-treatment of naloxone and cardamonin significantly (P < 0.001) reversed the effect of cardamonin on peak amplitude of compound action potential, suggesting the involvement of opioid receptors to inhibit nerve conduction. Conclusion: Cardamonin reduces the nerve signal conduction via activation of opioid receptors to modulate pain and contribute to the analgesic effects.

Matched MeSH terms: Naloxone
Indole alkaloids and anti-nociceptive mechanisms of Tabernaemontana divaricata (L.) R. Br. flower methanolic extract

Ali Khan MS, Misbah, Ahmed N, Arifuddin M, Rehman A, Ling MP

Food Chem Toxicol, 2018 Jun 05.
PMID: 29883785 DOI: 10.1016/j.fct.2018.06.007

Flowers of Tabernaemontana divaricata (L.) R. Br., (Apocynaceae) are used in traditional medicine for analgesic property. The present study was performed to isolate the active principles and investigate the mechanisms involved in the anti-nociception caused by T. divaricata flower methanolic extract (TDFME). The extract in the doses of 125, 250 and 500 mg/kg, p.o was subjected to various assays in acetic acid induced abdominal writhing and formalin induced paw licking test models. Naloxone, L-Arginine, Glibenclamide and Glutamate were used as inducers while Morphine, L-NAME, Methylene blue and Aspirin served as standard drugs. The phytochemical analysis led to the isolation of three indole alkaloids namely Voacangine, Catharanthine and O-acetyl Vallesamine. The anti-nociception produced by TDFME was attenuated significantly (p< 0.001) by the intra-peritoneal pretreatment of naloxone, L-Arginine and glibenclamide. The nociception produced by glutamate was inhibited by TDFME. TDFME also enhanced the antinociceptive activity of L-NAME when given in combination. However TDFME co-administration did not produce significant results with methylene blue indicating lack of cGMP involvement. These results indicate that TDFME produces anti-nociception action mediated by opioid, nitric oxide, K+-ATP and glutamate mechanisms and the effect is largely related to the indole alkaloids.

Matched MeSH terms: Naloxone
Fulltext In vivo analgesic effect of aqueous extract of Tamarindus indica L. fruits

Khalid S, Shaik Mossadeq WM, Israf DA, Hashim P, Rejab S, Shaberi AM, et al.

Med Princ Pract, 2010;19(4):255-9.
PMID: 20516700 DOI: 10.1159/000312710

To study the effects of Tamarindus indica L. aqueous fruit extract on the antinociceptive activities in rodent models.

Matched MeSH terms: Naloxone/pharmacology
Impact of capillary flow hydrodynamics on carrier-mediated transport of opioid derivatives at the blood-brain barrier, based on pH-dependent Michaelis-Menten and Crone-Renkin analyses

Yusof SR, Abbott NJ, Avdeef A

Eur J Pharm Sci, 2017 Aug 30;106:274-286.
PMID: 28614733 DOI: 10.1016/j.ejps.2017.06.016

Most studies of blood-brain barrier (BBB) permeability and transport are conducted at a single pH, but more detailed information can be revealed by using multiple pH values. A pH-dependent biophysical model was applied to the mechanistic analysis of published pH-dependent BBB luminal uptake data from three opioid derivatives in rat: pentazocine (Suzuki et al., 2002a, 2002b), naloxone (Suzuki et al., 2010a), and oxycodone (Okura et al., 2008). Two types of data were processed: in situ brain perfusion (ISBP) and brain uptake index (BUI). The published perfusion data were converted to apparent luminal permeability values, Papp, and analyzed by the pCEL-X program (Yusof et al., 2014), using the pH-dependent Crone-Renkin equation (pH-CRE) to determine the impact of cerebrovascular flow on the Michaelis-Menten transport parameters (Avdeef and Sun, 2011). For oxycodone, the ISBP data had been measured at pH7.4 and 8.4. The present analysis indicates a 7-fold lower value of the cerebrovascular flow velocity, Fpf, than that expected in the original study. From the pyrilamine-inhibited data, the flow-corrected passive intrinsic permeability value was determined to be P0=398×10-6cm·s-1. The uptake data indicate that the neutral form of oxycodone is affected by a transporter at pH8.4. The extent of the cation uptake was less certain from the available data. For pentazocine, the brain uptake by the BUI method had been measured at pH5.5, 6.5, and 7.4, in a concentration range 0.1-40mM. Under similar conditions, ISBP data were also available. The pH-CRE determined values of Fpf from both methods were nearly the same, and were smaller than the expected value in the original publication. The transport of the cationic pentazocine was not fully saturated at pH5.5 at 40mM. The transport of the neutral species at pH7.4 appeared to reach saturation at 40mM pentazocine concentration, but not at 12mM. In the case of naloxone, a pH-dependent Michaelis-Menten equation (pH-MME) analysis of the data indicated a smooth sigmoidal transition from a higher capacity uptake process affecting cationic naloxone (pH5.0-7.0) to a lower capacity uptake process affecting the neutral drug (pH8.0-8.5), with cross-over point near pH7.4. Evidently, measurements at multiple pH values can reveal important information about both cerebrovascular flow and BBB transport kinetics.

Matched MeSH terms: Naloxone/pharmacokinetics*

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