Antinociceptive and antioxidant activities of methanolic extract of leaves of Azadirachta indica in vivo

AbstractGraphical abstractBackgroundAzadirachta indica (Neem) is a communal plant of Meliaceae family called Neem Or Kadunimb in Maharashtra, India Neem stated anti-inflammatory through regulation of proinflammatory enzyme activities with COX and LOX enzyme. Previous studies show that Azadirachta Indica (neem) and its chief constituents play essential role in anticancer management via the modulation of different molecular pathways including NF-κB, p53, PI3K/Akt, Bcl-2, pTEN and VEGF. Many parts of the plant are traditionally used in the treatment of various pharmacological action, the analgesic activity of Neem Seed Oil has already reported but Neem Leaves.MethodsThe antinociceptive activity of Azadirachta Indica Leaves (AZIL) was examined using heat-induced-mechanical (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin, glutamic acid, cinnamaldehyde) nociception models in mice at 50,100, and 200 mg/kg doses. ATP-sensitive K+ channel pathway, cyclic guanosine monophosphate (cGMP) pathway and involvement of opioid system was also tested using glibenclamide, methylene blue and naloxone/morphine respectively. The methanolic extract of leaves of A.Indica was assessed by using different in vitro antioxidant models of screening like scavenging of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical.ResultsAZIL showed antinociceptive activity and antioxidant activity. In both hot plate and tail immersion tests AZIL significantly increases the latency to the thermal stimuli. In acetic acid-induced writhing test the extract repressed the number of abdominal writhing. Similarly, AZIL produced substantial dose-dependent inhibition of paw licking in both neurogenic and inflammatory pain induced by intraplanar injection of formalin. As well, AZIL also expressively withdrawn cinnamaldehyde-induced pain and the glutamate-induced pain in mice. It was also proved that pretreatment with naloxone significantly reversed the antinociception produced by AZIL in mechanical tests signifying the involvement of opioid system in its effect. Furthermore, administration of methylene blue, enhanced AZIL induced antinociception while glibenclamide, an ATP-sensitive K+ channel antagonist, could not converse antinociceptive activity induced by AZIL.ConclusionBased on the results of the present study it can be said that AZIL keeps significant antinociceptive activity which acts in both central and peripheral mechanisms.Ethnopharmacological relevanceAzadiracta Indica having family Melliases is one of the common medicinal plant in United states and south Asia including India, Pakistan, Bangladesh. Various parts of the plants used in treatment of many inflammatory conditions, skin diseases, tooth protection, antidiabetic in the form of oil and herbal porridge.

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Antinociceptive and Antioxidant Activities of Methanolic Extract of Leaves of Azadirachta Indica (Neem).

10.20944/preprints201907.0145.v1 ◽

2019 ◽

Author(s):

Akash Mali ◽

Mahesh B Thorat ◽

Dhairyasheel M. Ghadge ◽

Kumodini A. Nikam ◽

Shraddha D. Sawant ◽

...

Keyword(s):

Methylene Blue ◽

Acetic Acid ◽

Azadirachta Indica ◽

Methanolic Extract ◽

Antinociceptive Activity ◽

Opioid System ◽

K Channel ◽

Hot Plate ◽

Nitric Oxide Radical ◽

Tail Immersion

Background: Azadirachta indica (Neem) is a communal plant of Meliaceae family called Neem Or Kadunimb in Maharashtra, India Neem stated anti-inflammatory through regulation of proinflammatory enzyme activities with COX and LOX enzyme. Previous studies show that Azadirachta Indica (neem) and its chief constituents play an essential role in anticancer management via the modulation of different molecular pathways including NF-κB, p53, PI3K/Akt, Bcl-2, pTEN, and VEGF. Many parts of the plant are traditionally used in the treatment of various pharmacological action, the analgesic activity of Neem Seed Oil has already reported but Neem Leaves. Methods: The antinociceptive activity of Azadirachta Indica Leaves (AZIL) was examined using heat-induced-mechanical (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin, glutamic acid, cinnamaldehyde) nociception models in mice at 50,100, and 200 mg/kg doses. ATP-sensitive K+ channel pathway, cyclic guanosine monophosphate (cGMP) pathway and involvement of the opioid system were also tested using glibenclamide, methylene blue, and naloxone/morphine respectively. The methanolic extract of leaves of A.Indica was assessed by using different in vitro antioxidant models of screening like scavenging of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical. Results: AZIL showed antinociceptive activity and antioxidant activity. In both hot plate and tail immersion tests AZIL significantly increases the latency to the thermal stimuli. In the acetic acid-induced writhing test the extract repressed the number of abdominal writhing. Similarly, AZIL produced substantial dose-dependent inhibition of paw licking in both neurogenic and inflammatory pain induced by intraplantar injection of formalin. As well, AZIL also expressively withdrawn cinnamaldehyde-induced pain and the glutamate-induced pain in mice. It was also proved that pretreatment with naloxone significantly reversed the antinociception produced by AZIL in mechanical tests signifying the involvement of the opioid system in its effect. Furthermore, administration of methylene blue, enhanced AZIL induced antinociception while glibenclamide, an ATP-sensitive K+ channel antagonist, could not converse antinociceptive activity induced by AZIL. Conclusion: Based on the results of the present study it can be said that AZIL keeps significant antinociceptive activity which acts in both central and peripheral mechanisms.

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Antinociceptive and antioxidant activities of methanolic extract of leaves of Azadirachta indica in vivo

10.7287/peerj.preprints.27847 ◽

2019 ◽

Author(s):

Akash S Mali ◽

Mahesh B Thorat ◽

Dhairysheel M Ghadge ◽

Kumodini A Nikam ◽

Shraddha D Sawant ◽

...

Keyword(s):

Methylene Blue ◽

Acetic Acid ◽

Azadirachta Indica ◽

Methanolic Extract ◽

Antinociceptive Activity ◽

Opioid System ◽

K Channel ◽

Hot Plate ◽

Nitric Oxide Radical ◽

Tail Immersion

Background: Azadirachta indica (Neem) is a communal plant of Meliaceae family called Neem Or Kadunimb in Maharashtra, India Neem stated anti-inflammatory through regulation of proinflammatory enzyme activities with COX and LOX enzyme. Previous studies show that Azadirachta Indica (neem) and its chief constituents play essential role in anticancer management via the modulation of different molecular pathways including NF- κ B, p53, PI3K/Akt, Bcl-2, pTEN and VEGF. Many parts of the plant are traditionally used in the treatment of various pharmacological action, the analgesic activity of Neem Seed Oil has already reported but Neem Leaves. Methods: The antinociceptive activity of Azadirachta Indica Leaves (AZIL) was examined using heat-induced-mechanical (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin, glutamic acid, cinnamaldehyde) nociception models in mice at 50,100, and 200 mg/kg doses. ATP-sensitive K+ channel pathway, cyclic guanosine monophosphate (cGMP) pathway and involvement of opioid system was also tested using glibenclamide, methylene blue and naloxone/morphine respectively. The methanolic extract of leaves of A.Indica was assessed by using different in vitro antioxidant models of screening like scavenging of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical. Results: AZIL showed antinociceptive activity and antioxidant activity. In both hot plate and tail immersion tests AZIL significantly increases the latency to the thermal stimuli. In acetic acid-induced writhing test the extract repressed the number of abdominal writhing. Similarly, AZIL produced substantial dose-dependent inhibition of paw licking in both neurogenic and inflammatory pain induced by intraplanar injection of formalin. As well, AZIL also expressively withdrawn cinnamaldehyde-induced pain and the glutamate-induced pain in mice. It was also proved that pretreatment with naloxone significantly reversed the antinociception produced by AZIL in mechanical tests signifying the involvement of opioid system in its effect. Furthermore, administration of methylene blue, enhanced AZIL induced antinociception while glibenclamide, an ATP-sensitive K+ channel antagonist, could not converse antinociceptive activity induced by AZIL. Conclusion: Based on the results of the present study it can be said that AZIL keeps significant antinociceptive activity which acts in both central and peripheral mechanisms.

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Antinociceptive and antioxidant activities of methanolic extract of leaves of Azadirachta indica in vivo

10.7287/peerj.preprints.27847v2 ◽

2019 ◽

Author(s):

Akash S Mali ◽

Mahesh B Thorat ◽

Dhairysheel M Ghadge ◽

Kumodini A Nikam ◽

Shraddha D Sawant ◽

...

Keyword(s):

Methylene Blue ◽

Acetic Acid ◽

Azadirachta Indica ◽

Methanolic Extract ◽

Antinociceptive Activity ◽

Opioid System ◽

K Channel ◽

Hot Plate ◽

Nitric Oxide Radical ◽

Tail Immersion

Background: Azadirachta indica (Neem) is a communal plant of Meliaceae family called Neem Or Kadunimb in Maharashtra, India Neem stated anti-inflammatory through regulation of proinflammatory enzyme activities with COX and LOX enzyme. Previous studies show that Azadirachta Indica (neem) and its chief constituents play essential role in anticancer management via the modulation of different molecular pathways including NF- κ B, p53, PI3K/Akt, Bcl-2, pTEN and VEGF. Many parts of the plant are traditionally used in the treatment of various pharmacological action, the analgesic activity of Neem Seed Oil has already reported but Neem Leaves. Methods: The antinociceptive activity of Azadirachta Indica Leaves (AZIL) was examined using heat-induced-mechanical (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin, glutamic acid, cinnamaldehyde) nociception models in mice at 50,100, and 200 mg/kg doses. ATP-sensitive K+ channel pathway, cyclic guanosine monophosphate (cGMP) pathway and involvement of opioid system was also tested using glibenclamide, methylene blue and naloxone/morphine respectively. The methanolic extract of leaves of A.Indica was assessed by using different in vitro antioxidant models of screening like scavenging of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical. Results: AZIL showed antinociceptive activity and antioxidant activity. In both hot plate and tail immersion tests AZIL significantly increases the latency to the thermal stimuli. In acetic acid-induced writhing test the extract repressed the number of abdominal writhing. Similarly, AZIL produced substantial dose-dependent inhibition of paw licking in both neurogenic and inflammatory pain induced by intraplanar injection of formalin. As well, AZIL also expressively withdrawn cinnamaldehyde-induced pain and the glutamate-induced pain in mice. It was also proved that pretreatment with naloxone significantly reversed the antinociception produced by AZIL in mechanical tests signifying the involvement of opioid system in its effect. Furthermore, administration of methylene blue, enhanced AZIL induced antinociception while glibenclamide, an ATP-sensitive K+ channel antagonist, could not converse antinociceptive activity induced by AZIL. Conclusion: Based on the results of the present study it can be said that AZIL keeps significant antinociceptive activity which acts in both central and peripheral mechanisms.

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Atividade antinociceptiva e anti-inflamatória do extrato hexânico de "Echinodorus macrophyllus" (Kunth) Micheli em camundongos

Brazilian Journal of Health and Biomedical Sciences ◽

10.12957/bjhbs.2019.53056 ◽

2019 ◽

Vol 18 (1) ◽

pp. 25-32

Author(s):

Daniele C. Fernandes ◽

Bruna P. Martins P. Martins ◽

David L. F. Medeiros ◽

Shirley V. M. Santos ◽

Carlos R. M. Gayer ◽

...

Keyword(s):

Acetic Acid ◽

Fatty Acid ◽

Neurogenic Inflammation ◽

Ethics Committee ◽

Antinociceptive Activity ◽

Male Mice ◽

Hot Plate ◽

Fatty Acid Derivatives ◽

Tail Immersion ◽

Anti Inflammatory

Introduction: Echinodorus macrophyllus (Kunth) Micheli,Alismataceae, commonly known as “chapéu de couro”, isused in the treatment of various inflammatory conditions.The aim of this study was to evaluate the antinociceptiveand anti-inflammatory neurogenic potential and perform thephytochemical analysis of its hexanic extract (HEEm). Materialand methods: The HEEm was obtained by maceration ofdried leaves with hexane (100 g d.w./2 L). Its composition wasdetermined by GC-MS (DB1 column) by comparison of retentionindices in the database and literature. The antinociceptivepotential was evaluated in SW or DBA/1 male mice usingchemical (acetic acid and formalin), thermal (tail immersionand hot plate tests) and topical (xylene) nociception models,all approved by the Ethics Committee (CEA-IBRAG). Results:HEEM presented antinociceptive activity in the model of:acetic acid-induced writhing (52%; 25mg/kg); tail immersion(60 and 90 minutes; 50 mg/kg); hot-plate in 60 minutes (25and 100mg/kg) and 120 minutes (25mg/kg); formalin tests, atthe neurogenic (63.4%, 100mg/kg), and inflammatory (50%;50 and 100mg/kg) phases; and in neurogenic inflammationinduced by xylene (88.3%; 100mg/kg). These activities seem tobe related to the terpene and fatty acid derivatives evidencedby GC-MS. Discussion: HEEm presented antinociceptive, aswell as anti-inflammatory, activity by central and peripheralmechanisms, It consists of terpenic and fatty acid derivatives,described in the literature as antioxidants, anti-inflammatory,and antinociceptives. Conclusions: HEEm showed antinociceptiveactivity in all models, which can be related to thepresence of terpenic and fatty acid derivatives.Keywords: Echinodorus macrophyllus; Nociception;Neurogenic inflammation; Phytochemistry.

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Anti-nociceptive and anti-inflammatory effects of an aqueous extract of blended leaves of Ocimum gratissimum and Psidium guajava

Clinical Phytoscience ◽

10.1186/s40816-019-0130-2 ◽

2019 ◽

Vol 5 (1) ◽

Author(s):

Akinyinka O. Alabi ◽

Abayomi M. Ajayi ◽

Osarume Omorogbe ◽

Solomon Umukoro

Keyword(s):

Acetic Acid ◽

Aqueous Extract ◽

Psidium Guajava ◽

Antinociceptive Activity ◽

Hot Plate ◽

Hot Plate Test ◽

Promising Alternative ◽

Plate Test ◽

Ocimum Gratissimum ◽

Anti Inflammatory

Abstract Background To investigate the antinociceptive and anti-inflammatory activities of aqueous extract of a blended mixture of dried leaves of Ocimum gratissimum and Psidium guajava, a traditional analgesic drug polyherbal (TADP) used as a remedy for pain-related conditions. Methods Antinociceptive activity of TADP (100, 200 and 400 mg/kg) was evaluated in the hot plate test and acetic acid-induced nociception in mice while the anti-inflammatory was evaluated in carrageenan-induced paw oedema in rats. Levels of nitrite, myeloperoxidase, glutathione and malondialdehyde were assayed in carrageenan-induced paw tissue. Results TADP (200 and 400 mg/kg) significantly prolong the latency time in the hot-plate test. TADP (100–400 mg/kg) produced a dose-dependent significant inhibition of the acetic-acid induced abdominal constriction. The antinociceptive activity of TADP in the presence of naloxone and atropine was not reversed whereas yohimbine and glibenclamide significantly reversed it. TADP (100, 200 and 400 mg/kg) significantly reduced the swelling in the carrageenan-induced oedema model and also produced a reduction in the nitrite and myeloperoxidase level. TADP (400 mg/kg) significantly reduced malondialdehyde concentration and increase glutathione level in the carrageenan-induced rat paw. TADP significantly decrease the number of cellular infiltrates in the histopathological assessment. Conclusion These results indicate that polyherbal product containing blended leaves of Ocimum gratissimum and Psidium guajava possess antinociceptive and anti-inflammatory properties, hence represents a promising alternative remedy in inflammation-induced pain.

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In vivo and in silico evaluation of analgesic activity of Lippia alba

Clinical Phytoscience ◽

10.1186/s40816-019-0133-z ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 2

Author(s):

Md. Abdullah Aziz ◽

Manna Mehedi ◽

Mst. Irin Akter ◽

Sadiur Rahman Sajon ◽

Kishor Mazumder ◽

...

Keyword(s):

Acetic Acid ◽

Analgesic Activity ◽

In Silico ◽

Cyclooxygenase 2 ◽

Latency Time ◽

Hot Plate ◽

Standard Drug ◽

Lippia Alba ◽

Tail Immersion

Abstract Background This study was conducted to evaluate the analgesic activity of different extracts of Lippia alba (L. alba) along with in silico evaluation of analgesic activity of the isolated compounds from L. alba against cyclooxygenase-2 enzyme and ADME/T analysis of isolated compounds. Method In vivo analgesic activity of different extracts of L. alba was evaluated by acetic acid-induced writhing, tail immersion and hot plate on Swiss albino mice of either sex. In silico activity of the isolated compounds and ADME/T analysis were performed by Schrödinger-Maestro (Version 10.1) and OSIRIS Data warrior (version 4.6.1) softwares. Results Three different extracts (Methanolic extract: ME; Petroleum ether extract: PEE; Dichloromethane extract: DCME) of 250 mg/kg and 500 mg/kg doses were used in the experiments to evaluate analgesic activity. In acetic acid-induced writhing test, significant results were seen for PEE (500 mg/kg) and DCME (500 mg/kg), which were 53.09 ± 2.87 & 50.09 ± 4.24%, respectively. In tail immersion test, the best latency time was found at + 60 min for PEE (500 mg/kg) which is (5.65 ± 0.25) sec. For hot plate test, DCME at a dose 500 mg/kg showed the highest increase in latency time, which was 13.48 ± 0.33 s. In the case of in silico evaluation of analgesic activity, the compounds such as geranial, neral, (E)-caryophyllene, caryophyllene oxide, mussaenide, and 8-epi-loganin meet the condition of Lipinski’s rule of five. Among these safe compounds, 8-epi-loganin showed the best docking score of − 8.17 kcal/mol against cyclooxygenase-2 enzyme (PDB ID: 6COX), which was almost similar to that of the standard drug, Celecoxib (− 11.11 kcal/mol). Conclusion In conclusion, L. alba can be a potent source of analgesic medicine and further modification and simulation studies are required to establish the effectiveness of 8-epi-loganin.

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Ficus hispida Bark Extract Prevents Nociception, Inflammation, and CNS Stimulation in Experimental Animal Model

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7390359 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Md. Sariful Islam Howlader ◽

Md. Afjalus Siraj ◽

Shubhra Kanti Dey ◽

Arpona Hira ◽

Arif Ahmed ◽

...

Keyword(s):

Experimental Animal ◽

Antinociceptive Activity ◽

Bark Extract ◽

Thermal Stimulus ◽

Hot Plate ◽

Swiss Albino Mice ◽

Tail Immersion ◽

Ficus Hispida ◽

Albino Mice ◽

Anti Inflammatory

Background. Ficus hispida is traditionally used in the ailment of pain, inflammation, and neurological disorders. The present study set out to evaluate the in vivo antinociceptive, anti-inflammatory, and sedative activity of the ethanol extract of Ficus hispida bark (EFHB). Methods. The antinociceptive activity of EFHB was evaluated by using acetic acid induced writhing, formalin, hot plate, and tail immersion methods in Swiss albino mice. Its anti-inflammatory activity was assessed by using carrageenan and histamine induced rat paw oedema test in Wister rats. The central stimulating activity was studied by using pentobarbital induced hypnosis, hole cross, and open field tests in Swiss albino mice. Results. EFHB demonstrated antinociceptive activity both centrally and peripherally. It showed 62.24% of writhing inhibition. It significantly inhibited licking responses in early (59.29%) and late phase (71.61%). It increased the reaction time to the thermal stimulus in both hot plate and tail immersion. It inhibited the inflammation to the extent of 59.49%. A substantial increase in duration of sleep up to 60.80 min and decrease of locomotion up to 21.70 at 400 mg/kg were also observed. Conclusion. We found significant dose dependent antinociceptive, anti-inflammatory, and sedative properties of EFHB in experimental animal models.

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The Methanolic Extract fromMurraya koenigiiL. Inhibits Glutamate-Induced Pain and Involves ATP-Sensitive K+Channel as Antinociceptive Mechanism

Advances in Pharmacological Sciences ◽

10.1155/2016/3790860 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6

Author(s):

Nushrat Sharmin Ani ◽

Sudip Chakraborty ◽

Md. Moniruzzaman

Keyword(s):

Acetic Acid ◽

Potassium Channels ◽

Methanolic Extract ◽

Scientific Basis ◽

K Channel ◽

Dependent Manner ◽

Glutamatergic System ◽

Antinociceptive Effects ◽

Wide Range ◽

Antinociceptive Mechanisms

Murraya koenigiiL. is a perennial shrub, belonging to the family Rutaceae. Traditionally, the leaves of this plant are extensively used in treatment of a wide range of diseases and disorders including pain and inflammation. Although researchers have revealed the antinociceptive effects of this plant’s leaves during past few years, the mechanisms underlying these effects are still unknown. Therefore, the present study evaluated some antinociceptive mechanisms of the methanolic extract ofM. koenigii(MEMK) leaves along with its antinociceptive potential using several animal models. The antinociceptive effects of MEMK were evaluated using formalin-induced licking and acetic acid-induced writhing tests at the doses of 50, 100, and 200 mg/kg. In addition, we also justified the possible participations of glutamatergic system and ATP-sensitive potassium channels in the observed activities. Our results demonstrated that MEMK significantly (p<0.01) inhibited the pain thresholds induced by formalin and acetic acid in a dose-dependent manner. MEMK also significantly (p<0.01) suppressed glutamate-induced pain. Moreover, pretreatment with glibenclamide (an ATP-sensitive potassium channel blocker) at 10 mg/kg significantly (p<0.05) reversed the MEMK-mediated antinociception. These revealed that MEMK might have the potential to interact with glutamatergic system and the ATP-sensitive potassium channels to exhibit its antinociceptive activities. Therefore, our results strongly support the antinociceptive effects ofM. koenigiileaves and provide scientific basis of their analgesic uses in the traditional medicine.

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Antinociceptive Activities of the Methanolic Extract of the Stem Bark ofBoswellia dalzieliiHutch. (Burseraceae) in Rats Are NO/cGMP/ATP-Sensitive-K+Channel Activation Dependent

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/6374907 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Marius Mbiantcha ◽

Alain Ngouonpe Wembe ◽

Amadou Dawe ◽

William Yousseu Nana ◽

Gilbert Ateufack

Keyword(s):

Methylene Blue ◽

Neuropathic Pain ◽

Methanolic Extract ◽

Stem Bark ◽

Opioid Antagonist ◽

K Channel ◽

Therapeutic Effects ◽

Pain Models ◽

Antinociceptive Effects ◽

Oxide Synthase

Boswellia dalzielii (B. dalzielii)is traditionally used in the treatment of rheumatism, pain, and inflammation. The present investigation evaluates the property and possible mechanism of action of the methanolic extract ofB. dalzielii(BDME) on inflammatory and neuropathic pain models. Effects of BDME (250 and 500 mg/kg), orally administered, were verified in mechanical hypernociception induced by LPS or PGE2. Mechanical hyperalgesia, cold allodynia, and heat hyperalgesia were used in vincristine-induced neuropathic pain. NW-nitro-L-arginine methyl ester (inhibitor of nitric oxide synthase), glibenclamide (ATP-sensitive potassium channel blocker), methylene blue (cGMP blocker), or naloxone (opioid antagonist receptor) has been used to evaluate the therapeutic effects of BDME on PGE2-induced hyperalgesia. Chemical profile of BDME was determined by using HPLC-XESI-PDA/MS. BDME showed significant antinociceptive effects in inflammatory pain caused by LPS and PGE2. The extract also significantly inhibited neuropathic pain induced by vincristine. The antinociceptive property of BDME in PGE2model was significantly blocked by L-NAME, glibenclamide, methylene blue, or naloxone. The present work reveals the antinociceptive activities of BDME both in inflammatory and in neuropathic models of pain. This plant extract may be acting firstly by binding to opioid receptors and secondly by activating the NO/cGMP/ATP-sensitive-K+channel pathway.

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