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Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S43

Contents lists available at ScienceDirect Asian Pacific Journal of Tropical Medicine

journal homepage:www.elsevier.com/locate/apjtm

Document heading doi: 10.1016/S1995-7645(14)60202-9 A review study on applications of Iranian medicinal

1 2 3 2 2 Mahmoud Bahmani , Hedayatollah Shirzad , Maedeh Majlesi , Najmeh Shahinfard , Mahmoud Rafieian-Kopaei * 1Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran 2Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran 3Faculty of Nursery and Midwifery, Iran University of Medical Sciences, Tehran, Iran

ARTICLE INFO ABSTRACT

Article history: Numerous side effects of synthetic have caused medicinal plants to be regarded in recent Received 21 Jul 2014 decades as a reliable source of new drugs. Regarding the analgesic effects of many plants that are Received in revised form 4 Aug 2014 pointed in of Iran, many studies have been performed in this field that have Accepted 20 Aug 2014 caused need to be reviewed. In this study, different methods of testing pain, analgesic activity Available online 19 Sep 2014 and possible compounds of medicinal plants and also the possible mechanisms actions of these T Keywords: plants are presented. he data presented in this review paper provide scientific information that might be used for isolation of potentially active compounds from some of these medicinal plants Analgesia in future. Antinociception Medicinal plants Pain

1. Introduction involving in pain conditions are partially or totally disabled. The United States Center for Healthcare Statics carried out Based on definition of international association of an eight-year study, demonstrating 32.8% U.S. populations pain study, pain is an undesirable mental and emotional were suffering from chronic pain[7]. experience that is associated with possible or actual Recent studies have shown that 22% of primary care damage of tissue or is created in some periods of these patients suffered from pain which persists for more than six types of pains. Pain is created by different reasons months and in some cases the percentage rises to 50% which such as harmful heat, stretch, electrical flow, necrosis, is related to significant impairment of social functioning inflammation, laceration and spasm[1]. Pain is also caused and quality of life[8]. by a wide variety of diseases, surgical interventions and Although pain mainly is considered as a defense trauma. Degenerative diseases like rheumatoid arthritis, mechanism which is created when a tissue is damaged and polymyalgia rheumatica, as well as heart, asthma, cancer caused a person show reaction and remove pain [4], and inflammatory bowel diseases are also associated with however, in sever condition it impairs social functioning inflammatory processes and pain. It is a complex experience and reduces quality of life[1]. in which cognitive, affective and behavioral features, Millions of people suffering from different types of representing psychological conditions are affected[2]. In damage who wish to find a with more effect and less most cases, pain is secondary to other complications such side effects in order to release themselves from the pain[9]. as diabetic nephropathy[3-6]. Medicinal plants have been suggested to presence natural More than 50 million American populations due to effective substances for prevention or treatment of pain related conditions. Drugs with herbal origin have attracted *Corresponding author: Mahmoud Rafieian-Kopaei, Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran. attention of researchers and people by having low or no E -mail: [email protected] side effects[10,11]. These medicinal plants mostly possess Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S44 antioxidant activities[3,12-16], and other than pain and belong to big family of G receptors of protein (GPCRs) and inflammation, are effective on a lot of hard curable diseases committed to control GABA and glutamate. Metabotropic such as diabetes and cancer which may increase free glutamate receptors and metabotropic GABA receptors have radicals and result in pain[6,17-20]. play in different levels of pain that control pain transfer[25]. This paper was aimed to present Iranian medicinal plants Recently it has been determined that glutamate interferes which are used and shown promising results for prevention in transferring sensory input especially during pain and treatment of pain and inflammation. The paper not transferring[26]. only presents different kinds of pain, mediators of pain and 3.2. Substance P inflammation but also discusses the pathophysiology of pain.

Secretion of substance P through axon distributions in 2. Acute and chronic pain skin causes vasodilation, blood capillaries dilation and release of histamine from mast cells. Sensitivity of pain Pain is divided into two main types: rapid or fast and receptors surrounding surgery place causes secondary slow pain. Rapid pain is felt one second or more after through substance P and causes secondary hyperalgesia[27]. stimulant strike and then its severity is increased slowly Substance P is available inside some primary sensatory during several seconds or even minutes[20]. Fast pain is neurons that terminate to surface area of dorsal horn of described by some names like electrical, acute, tingling, and spinal cord. Intensive stimulation of primary afferent fibers stabbing pain. Slow pain also has different names including distributions that activate A-delta and C-delta fibers, cause unclear, chronic, throbbing and burning pain. This type of secretion of substance P[28]. pain is accompanied by tissue destruction and can lead to 3.3. Serotonin unbearable pain. This pain almost can be created in both skin and tissue or deep organism[2]. Fast pain mainly is created by mechanical or heat painful stimuli while slow Many neurons in raphe nuclei secrete serotonin as a and chronic pain is more stimulated by painful chemical neurotransmitter. Serotonin can inhibit pain neurons and [1]. Pain is described as one of the five critical possibly plays an important role in endogenous anti-pain signs that many negative outcomes are created if it is not system. Other neurons of brainstem release epinephrine and regarded[2]. norepinephrine in spinal cord. These neurons also inhibit pain neurons[29]. 3. Pain mediators 3.4. Histamine

High ratio of somatic or visceral pain receptors can Histamine has main role in allergic inflammation. be stimulated or sensitized by different stimulants and Inflammatory responses resulted by histamine release are inflammatory mediators like bradykinin, prostaglandins, long and performed by mediator of histamine receptor leukotrienes, serotonin, histamine, capsaicin and free H1. Antagonists of H1 receptors are usually recognized radicals[21-23]. The following cases can be mentioned on pain as antihistamines and have been used to treat allergy for mediators. many years. Discovery of histamine four receptor and its expression in different inflammatory cells make it possible 3.1. Glutamate to reevaluate histamine functions[30].

3.5. Nervous growth factor (NGF) Amino acid stimulated by glutamate can perform through ion channels dependent to ligand (glutamate ionotropic receptors) or glutamate metabotropic receptor (mGLuRs) This factor possibly interferes in inflammatory pain coupled with G protein[24]. Glutamic acid and gamma amino directly or indirectly. Inflammatory mediators like cytokines, butyric acid (GABA) is respectively two main nervous increase production of NGF in inflamed tissues[31]. NGF excitatory and inhibitory transferor of central nervous system stimulates mast cells in releasing of histamine and serotonin. in mature mammals. These transferors perform through Also this factor can stimulate thermal hyper allergy directly two metabotropic and ionotropic receptors. Ionoteropic through performing on peripheral terminals of primary receptors are ligand-gated ion channels that are involved afferent fibers[32]. NGF is a member of neurotrophin family in rapid synaptic transfer while metabotropic receptors and is determinant of survival of pain neurons. Recently Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S45 important role in pain performance has been shown for it Repeated administration of them results in three states: in adults. This factor in skin causes thermal hyper-allergy tolerance, physical and mental dependence. during a few minutes. Mast cells are important components Tolerance is occurred after repeated use of drugs in action of NGF[33]. and the person needs to keep increasing the amount used to achieve that first effect. Consumed , like , 3.6. Adenosine and adenosine phosphate δ κ μ affect on opioid receptors ( , , ) with internal origin and decrease peptides with internal origin by a negative Inflammation and tissue damage possibly release feedback[40]. Morphine has been used for many centuries, adenosine and adenosine phosphate [adenosine but is not free of side effects. Respiratory problems, napping, monophosphate, adenosine diphosphate, adenosine decrease in gastrointestinal mobility, nausea, and changes triphosphate (ATP)] and secret into extracellular space in automatic nervous system and endocrine secretion are and activate pain receptors[33]. ATP receptors are found some of the morphine side effects[41]. in primary sensory nerves of dorsal root ganglion and in 4.2. Nonsteroidal anti-inflammatory drugs peripheral nerves. ATP possibly activates pain neurons in healthy skin through P2X2-P2X3 receptors and purinergic P2X3 receptors[34]. Nonsteroidal anti-inflammatory drugs are used extensively to control chronic pain. These drugs inhibit cyclooxigenase 3.7. Indigenous enzyme and have three important properties: decreasing inflammation, pain and . Depending on the drug, this Indigenous cannabinoids are a family of bioactive lipids group has renal, digestive and even cardiovascular effects[2]. that activate receptors to regulate nervous 4.3. Topiramate transfer. They are available in brain in low amounts and participate in regulating different brain functions including pain perception, appetite and memory. They are produced Topiramate has been approved by Food and Drug in level of postsynaptic terminals that need calcium Administration in America as anti-migraine drug. ion penetration and spread in surface of presynaptic Topiramate has been revealed to increases activity of cannabinoid receptors[35]. Irritant stimulant increases GABA receptors by inhibiting voltage-dependent calcium indigenous cannabinoid spread. This action expresses their and sodium channels and inhibits glutamate metabotropic role in regulation of pain[36]. Endocannabinoids decrease receptors[2]. pain. Natural and artificial cannabinoids have ability to decrease pain feeling, inflammation, inflammatory pain, 5. Methods of testing pain in animals hyper allergy and prevent secondary tissue damage in traumatic wounds[37]. 5.1. Hot plate test

4. In this method, mice are individually put on plate 3-4 times in 3-5 min intervals to decrease nervous pressure. Although a wide variety of different drugs from various The time duration between placing mice on plate and groups have analgesic activities, opioids and nonsteroidal licking time is considered as threshold and delay of licking anti-inflammatory drugs are the two main groups of drugs or kicking time by animal in different times is recorded. which are used to combat pain. To calculate more exactly, each mouse is put on plate for 4-5 times in 5 min intervals and the average is obtained. Cut 4.1. Opioids off time to avoid tissue damage is considered for animal[42]. Pain control mechanisms are introduced in this test[32]. Hot Opioids perform their effects through binding to special plate test is a selective test for opioid-like compounds[33]. types of opioid receptors which exist throughout the brain This test is an extra-spinal pain model. The main property of and spinal cord[38,39]. Morphine is the first natural opioid and this test is able to provide automatic defensive behaviors[43]. its effects were determined. Further research in mammals 5.2. Writhing test led to identification of opioids with internal origin and also receptors of these opioids. Encephalin and endorphins, especially beta endorphin, are of endogenous opioids. In this test, acetic acid solution is injected to mice, Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S46 intraperitoneally. Then the number of writhing is recorded calculated for each mouse. After calculating mean threshold for 30 min after injection of acetic acid[39]. Provided writhings in each mouse, the percent of analgesia index is calculated include contractions of abdominal muscles followed by according to below formula[44]: [44] opening back feet or stretching all body in animal . Drug latency-Control latency × C Analgesia index= 100 ontractions of abdominal muscles depend on sensitivity of Cut off time-Control latency pain receptors to compounds like prostaglandins. 5.5. Formalin test Tissue damage causes release of compounds like prostaglandins, bradykinin, serotonin, substance P, α histamine and PGF2 and causes expression of inflammatory In this method, a glass container is used to placing animal pain by induction of capillary permeability. Analgesic in it and observing animal responses. A mirror is positioned ° activity of opioid agonists and non-steroidal anti- underneath the container and is set at a 45 angle to secure µ inflammatory drugs can be determined by this test. In a clear vision. To perform test, 20 L of 2.5% formalin is addition to prostaglandins, several inflammatory mediators injected subcutaneously into the surface of the paw. Then α including tumor-necrosis-factor- and interleukins are time durations of licking/biting of the formalin-injected paw also contributed to nociceptive response to acetic acid. Also is recorded during two delay and rapid stages. Usually early response of this test depends on macrophages activity and 0-5 min is called acute phase and late 5-60 min is called peritoneal mast cells. Macrophages stimulate arachidonic chronic phase[45]. acid release and formation of F2 or E2 prostaglandins by secretion of bradykinin. Mast cells synthesize inflammatory 6. Effects of medicinal plants extracts on pain mediators including interleukins, placket activating factor, granulocyte-macrophage stimulating factor, macrophage inflammatory protein and arachidonate metabolites, Due to potential side effects and low efficacy of synthetic prostaglandins and leukotrienes[34]. and chemical drugs, consumption of other complementary drugs especially herbal remedies to control pain is 5.3. Light tail flick test increasing[11]. Effects of herbal extracts have been studied by different pain tests including writhing test, light tail flick In the light tail flick, the mouse is placed in restrainer test, tail immersion, hot plate test and formalin tests. device in a way that animal tail is outside chamber. In this Different extracting methods have also been used in order method, the lamp light is used to create pain. Light beam to produce extracts that the most frequently methods are is focused on tail and after a while, the animal flicks its tail percolation, Soxhlet and maceration[46-48]. The extracts in result of pain created by heat. At first, animal tolerance are often aqueous, ethanolic, hexane, ethyl acetate and - is measured and the tolerance time is considered as control aqueous ethanolic types[49-53]. Some of the are plants Saliva hydrangea, Thymus latency. Then, in different intervals, up to 120 min after drug presented in Table 1, such as vulgaris, Melissa officinalis, Menthe pulegium, Ziziphora administration, the pain tolerance time duration is recorded tenuior Stachys lavandulifolia Gundelia tournefortii again and maximum analgesic response is calculated by the , , L., stramonium Solenanthus circinnatus Carum below formula: L., , copticum Apium graveolens Allium jesdanum Pistacia vera - , , , Test latency Control latency × Vitex agnus Sambucus ebulus Portulaca oleracea Piper Maximum analgesic response= 100 L., , , , Cut off time-Control latency nigurm Juglans regia Melilotus officinalis Matricaria , , , chamomilla Artemisia herba Crocus sativus Foeniculum Cut off time is the maximum tolerance time to prevent , , , vulgare Colchicum szovitsii Elaeagnus angustifolia animal tail damage[40]. , , and which have analgesic effects in traditional medicine. Among 5.4. Tail immersion plants which their analgesic effects have been proved, the most effective species belongs to Lamiaceae family. Hot water tail immersion test or briefly tail immersion is Plants affecting pain, in addition to analgesic properties, used to study acute pain. First, mouse is put into restrainer have different therapeutic properties. For example, ’ and after 20 min, mouse s tail is immersed into the hot water ability to treat rheumatism, gout, migraine, relax muscle, bath. Time duration of placing tail in water until mouse wound healing, antispasmodic[54-56], anti-inflammation, withdraws its tail from water is considered as acute pain edema, anti-blood pressure[57,58], antioxidant, anti- threshold. Tail of each mouse is placed in water 5 times hormonal[59,60], antiviral[61], antimicrobial[62], preventing in 7 min intervals and mean threshold of these times is Alzheimer, reinforcing memory[63], anti-diabetes[64,65], renal, Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S47 Table 1

Some important medicinal plants with antinociceptive activity. Family name Scientific name Pain test type Fractions and used organism Possible mechanism Reference Saliva hydrangea Lamiaceae Light tail flick Essence and hydroalcoholic extract of leave and flower Inhibiting synthesis path of prostaglandins 73 Lavandula officinalis Tail flick and formalin test Methanolic Effect on inflammatory processes 74,75 [Labiatea] Thymus vulgaris Tail flick hot plate hydroalcoholic - 76 Melissa officinalis Tail flick Aqueous extract of branches Central anti-pain mechanism 77 Menthe pulegium Formalin test Aqueous-alcoholic extract of leave Inhibiting NO synthesis, inflammatory mediators and NMDA 78 receptors and irritating opioid receptors Teucrium hyrcanicum Formalin, tail flick and writhining Aqueous extract of leave Inhibiting prostaglandins synthesis and central nervous system 79 Salvia hypoleuca Formalin test Alcoholic extract of leave Opioid system and inhibiting pre-inflammatory mediators 80 Ziziphora tenuior Writhing test Aqueous-alcoholic extract of leave and branches Inhibiting release of acid arachidonic and synthesis of 81 prostaglandins and effect on opioid system Teucrium polium Tail flick test Aqueous Binding to pain receptors, affecting ligand-sensitive channels and 82 decreasing sodium entrance Origanum vulgare L. Tail flick test Aqueous Antioxidant compounds, inflammatory processes and opioid receptors 83 Satureja hortensis Linn. Formalin, tail flick test Aqueous extract of seed Through central mechanisms and inflammatory processes 84 Salvia sclarea Formalin, tail flick and writhing test Alcoholic extract of aerial and hydroalcoholic parts of leave Peripheral effects and inflammatory processes and opioid receptors 85 Mentha piperita Linn. Formalin, hot plate and writhing test Alcoholic extract of leave Peripheral and central effects 45 Stachys lavandulifolia Formalin and tail immersion test Hydroalcoholic extract of branches Inhibiting cyclooxigenase 86 Artemisia dracunculus Asteraceae Formalin test Leave powder (edible prescription) Presence of flavonoids and some substances with benzodiazepines 87 property Matricaria chamomilla Formalin test Chamamill Cholinergic mechanisms 88 Gundelia tournefortii L. Formalin test Aqueous-alcoholic extract of aerial branches Serotonergic, GABAergic and adrenergic and inflammatory processes 89 Tanacetum parthenium Hot plate Alcoholic extract of aerial organisms Inflammatory processes 89 Solanum melongena Formalin test Hydroalcoholic extract of fruit Peripheral anti-pain mechanisms and cholinergic paths 90 niger Tail immersion Alcoholic extract of seed Opioid and cholinergic mechanisms 91 Datura stramonium L. Formalin and hot plate test Alcoholic extract of seed Reinforcing opioid system and decreasing peripheral and central 92 hyperalgesia mediators Solenanthus circinnatus Boraginaceae Formalin and tail flick Hydroalcoholic extract of root Through inhibiting central and peripheral paths 93 Euphorbia helioscopia Euphorbiaceae Writhing test Alcoholic extract of aerial sections Effect of flavonoids and steroids 46 Carum copticum Umbelliferae Formalin Aqueous and oil extract of fruit Effect of essential fatty acids 94 Dorema aucheri Formalin Aqueous-alcoholic extract of aerial parts Inhibiting NO synthesis and NMDA receptors and irritation of opioid 95 and adrenergic system Petroselinum crispum L. Formalin and acid acetic test Alcoholic extract of leave Activating anti-pain paths 96 Apium graveolens Formalin Hydroalcoholic extract of fruit Inhibition of cyclooxigenase 97 Allium jesdanum Lilaceae Hot plate and tail flick Aqueous- alcoholic extract of leave Central anti-pain properties and affecting on opioid receptors 98 Pistacia vera Anacardiaceae L. Hot plate, writhing and formalin test Hydroalcoholic extract of resin Inhibiting opioid receptors and inflammatory mediators 99 Sambucus ebulus Adoxaceae Writhing and hot plate Hexane, ethyl estate and methanolic extract of fruit, Inhibition of prostaglandins synthesis 98 leave and root Vitex agnus castus Verbenaceae formalin test Hydroalcoholic extract of fruit Inhibition of prostaglandins synthesis and other inflammatory mediators 100 Coriandrium sativum Apiaceae formalin test Aqueous extract of seed - 101 Trigonella foenum- Fabaceae formalin test Aqueous extract of leave Effect of serotonergic system graecum 102 Portulaca oleracea Portulacaceae Hot plate and tail flick Aqueous- alcoholic extract of aerial sections Central and peripheral effects 103 Phoenix dactylifera β Palmaceae Formalin, tail flick and paw pressure Aqueous extract of fruit Increase of blood carbohydrates and -endorphins level and 104 peripheral mechanisms Cinnamomum Lauraceae Formalin Aqueous-alcoholic extract of stem skin Inhibiting NO synthesis and COX2 and inhibition of prostaglandins zeylanicum 70 production and irritation of opioid receptors Artemisia siberi Artemisia Besser. Formalin Aqueous-alcoholic extract of branches Inhibiting calcium release, blocking TRPAI receptors, inhibiting NO 104 synthesis and cytokines and prostaglandin E2 Artemisia herba-alba Formalin, tail flick Aqueous-alcoholic extract of stem and leave Irritation of GABA A receptors 105 Humulus lupulus Cannabaceae L. Formalin Aqueous extract of plant Opioid receptors 106 Foeniculum vulgare Apiaceae Formalin Aqueous extract of fruit Serotonergic and hystaminergic receptors 79 Crocus sativus Iridaceae Formalin Aqueous extract of flower Possible inhibition of NMDA receptors and nitric oxide synthesis 107 Zingiber oficinalis Zingiberaceae , Z.o Formalin Alcoholic extract of rhizome Inhibiting release of peripheral mediators, cytokine, TNF and β 108 interleukin-1 , nuclear factor kappa B Cuminum cyminum L. Formalin Aqueous extract of fruit - 2 Elaeagnus angustifolia Elaeagnacea Formalin and writhing test Aqueous extract of fruit and leave Inhibiting pre-inflammatory mediators and NMDA receptors 109 Drosera spatulata Droseraceae Formaline Aqueous extract of plant Activity of paragigantocellularis cell 110 Glycyrrhiza glabra Fabaceae Formaline and tail flick test Hydroalcoholic extract of root Inhibiting immigration of white globules and production of 111 inflammatory meditators and Neutrophils Hypericum perforatum Hypericaceae Formaline and tail flick test Aqueous extract of flowering branches Inhibiting COX1 and 5-LO enzyme 65 Piper nigurm Piperaceae Formaline test Methanolic extract of fruit Central and anti-inflammatory 112 Juglans regia Juglandaceae Formaline test Alcoholic extract of leave Inhibiting COX1 enzyme, calcium release inhibiting and 113 cholinergic, histamine and adrenergic mechanisms Rosa demascena Rosaceae Hot plate and tail flick test Alcoholic, aqueous and extract of flower Opioid system 114 Glaucium grandiflorum Papaveraceae Formaline and hot plate Methanolic extract of aerial parts 115 Matricaria chamomilla Comositeae Formaline and hot plate Methanolic extract of flower Inflammatory processes 116 Lactuca sativa longifolia Formaline and tail flick test Aqueous-alcoholic extract of leave Central and peripheral mechanisms 117 Securigera securidaca Papilionaceae L. Formaline test Hydraualcoholic extract of seed Inhibiting NO and COX2 synthesis 118 Melilotus officinalis Leguminosae Formaline and tail flick test Methanolic extract of fruit Opioid system 119 Berberis vulgaris Berberidaceae L. Formaline test Aqueous-alcoholic extract of root Opioid system 120 NMDA: N-methyl-D-aspartate. Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S48 digestive and respiratory effects[66-68], increasing secretive calcium-dependent phospholipase A2 is decreased and activity and digestive movement[69,70], anti-anxiety, and in result by decreasing NO and prostaglandins show their abortifacient effects[71,72]. Their compounds affecting on pain analgesic effects. Inhibiting phospholipase A2 enzyme include flavonoids (quercetin), volatile oils (monoterpenes activity inhibits transformation of phosphatidic acid to and sesquiterpenes), phenolic compounds like thymol and arachidonic acid and in result synthesis of prostaglandins carvacrol, coumarin, glycoside steroids, compounds is inhibited[123]. Regarding available evidence, flavonoids arachidonic like , and hyoscine, organic acids inhibit production of prostaglandin [E] from like caffeic acid, rosmarinic acid, nicotinic acid, as well as acid in response to inflammatory stimulants by inhibiting phenolics, GABA, tannins, essential oils, pinene, limonene TNF and inhibiting cyclooxigenase enzyme[118,124]. and cineol, monoterpenes, alcohols, diterpenoids, riboflavin, Flavonoids including apigenin decrease accumulation terpenes, resins, iridoids, saponins, cineol, myrcene, of floating lipids that are necessary to signal pain so they α -thujene and camphor. reduce inflammatory pain by inhibiting accumulation of receptors and hormonal cascade[97]. Flavonoids available in Artemisia dracunculus decrease pain by protective property 7. Discussion against oxidative stress resulted from hyperglycemic state and substances with property similar to benzodiazepines[119]. Pain is a response including emotional, sensory and Direct effect of flavonoids on prostaglandins synthesis has mental sections. Disease, inflammation and damage to been proved. Since NO is hyperalgesia mediator, so its peripheral and central nervous system cause clear changes decrease leads to analgesic activity. Flavonoids interfere in pain paths like change in gene expression and increase in pain regulation through opioid system and adrenergic in production of molecules like neurotransmitters, enzymes system. Among essential oils the compound alpha- and receptors. Suffering from pain in long term imposes eudesmol is inhibitor of omega-toxin-sensitive P/Q type undesirable mental effects. So, human has been always calcium channels sensitive to omega toxin so can inhibit seeking to a solution to decrease or eliminate pain[59]. Pain release of neurotransmitters from terminals of pain fibers is a phenomenon considered as a warning factor but it is an in posterior horn of the spinal cord and finally decreases undesirable feeling and human has tried to resist it. Analysis pain[111]. Glycyrrhizin is one of the compounds available in Glycyrrhiza glabra of researches made in recent decades demonstrates special that applies its anti-inflammation effect attention paid to analgesic drugs, since analgesic drugs by inhibiting immigration of white globules toward inflamed available in medicinal market show an extensive range of areas and inhibiting production of inflammatory mediators Glycyrrhiza glabra undesirable side effects[110]. in neutrophils. Edible use of causes β Flavonoids are natural polyphenol compounds available inhabitation of 11- dehydrogenase enzyme and in following in plants that have analgesic and anti-inflammation increase in level of blood cortisol. Possibly this substance properties[118]. Flavonoids can pass through brain-blood decreases pain in the second phase of formalin test through barrier and control pain by different mechanisms like decreasing inflammation[111]. affecting GABA A, opioid, a-adrenergic receptors and Tannin, menthol and menthone are analgesic compounds inhibiting enzymes involved in inflammation in brain. in plants. Studies show that menthol has specific receptors Presence of GABA A, opioid, and adrenergic receptors is in the cell membrane that leads to decrease in intracellular reported in different areas of nervous system including current in the rest state and increases pain threshold of in rostral ventrolateral medulla that paragigantocellular cells. This compound decreases inward calcium current, nucleus is a part of it. Irritation of these receptors causes irritability and amount of synaptic transfer by affecting pain relief[121,122]. Flavonoids, by inhibiting cyclooxigenase calcium channels available in nervous cells membrane in tissues, prevent formation of prostaglandins. especially pain path neurons and leads to decreased pain Prostaglandins cause stimulation of pain receptors. perception. Regarding effect of menthol on kappa opioid Plants containing flavonoids perform many of their effects receptors, possibly menthol available in plants extracts by inhibiting the cyclooxigenase enzyme[44]. Flavonoids are affect on these receptors and so inhibits current and transfer considered as the inhibitors of synthesizing enzyme nitric of pain signal and leads to decrease in pain perception[78]. Portulaca oxide and prevent NO production that is increased following Extract of some plants like or parsley possibly formalin injection, so its decrease leads to analgesic activity. apply their effects by activating systems interfering in Other studies show that flavonoids, by inhibiting activity analgesic paths like opioidergic, GABAergic, cholinergic of NMDA receptors, decrease intracellular calcium and in and glutamatergic systems[103]. following activity of synthesizing enzyme, nitric oxide and Inhibiting metabolism of arachidonic acid and nitric Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S49 oxide syntheses enzyme has been suggested for terpene influencing opioids[117]. available in compounds. Also linalool is one of the monoterpene inhibits activity of enkephalinase enzyme and applies compounds in cinnamon that affect on pain receptors and analgesic effect by maintaining encephalin[117]. causes analgesia. It seems that terpenoids, flavonoids and alkaloids impose Linalool creates inhibitory capability in central nervous analgesic effects through inhibiting prostaglandins synthesis system neurons by opening potassium channels. Phenols and central nervous system. Also terpenes, essential and like eugenol inhibit calcium entrance inside cell and so volatile oils have analgesic effect[75]. control release of neurotransmitters interfering in pain from terminals of afferent fibers in posterior horn of the spinal 8. Conclusion cord[90]. Phenolic monoterpenes like thymol and carvacrol have inhibitory effects on prostaglandins[125]. Gingerol substance as effective constituent of rhizome of ginger has There are various kinds of mediators such as ability to inhibit production of prostaglandins, leukotrienes prostaglandins, cytokines, histamine, serotonin, substace and kinin as the most important inflammatory mediators. P, capsaicin, and nitric oxide which cause pain and Moreover, it causes inhabitation of release of cytokines inflammation. Pain is created by different reasons such as types, TNF and interleukin-1B and decrease of kappa factor harmful heat, stretch, electrical flow, necrosis, inflammation, by this extract. Ginger extract decreases production of NO laceration and spasm[6]. Pain is also caused by a wide variety and prostaglandin E2. These compounds are important of diseases, surgical interventions and trauma. Degenerative mediators of vascular permeability increase. Decrease diseases like rheumatoid arthritis, polymyalgia rheumatica, of vascular permeability and production of pain and as well as heart, asthma, cancer and inflammatory bowel inflammation mediators is considered as the most important diseases are also associated with inflammatory processes inflammation reducing factors and consequently pain by and pain. Medicinal plants have been suggested to presence ginger[108]. reliable remedies for prevention and treatment of pain Alcoholic compounds like camphor causes decrease related conditions. Traditional medicine in Iran can be used in inflammatory pain. Camphor prevents transient for pain-related ailments. The data presented in this review receptor potential V1 cation channels (also known as paper provides scientific information that might be used for the capsaicin receptors), to be sensitized, so it has anti- isolation of potentially active compounds from some of these pain effects. Camphor inhibits synthesis of NO, cytokines medicinal plants in future. and prostaglandins E2. Also it causes inhibition of calcium release. Phenolic compounds like thymol imitate Conflict of interest statement parasympathetic effects[126]. Hypericum perforatum Aqueous extract of causes analgesia α through serotonergic, -2 adrenergic and opioidergic We declare that we have no conflict of interest. mechanisms by inhibiting COX1 enzyme. It has been observed that sensory fibers are sensitized after release Acknowledgement leukotrienes from damaged fibers. This sensitization is provided through B4 and D4 leukotrienes that are of This review paper was prepared by the support of metabolites of lipoxygenase. Lipoxygenase inhibitors prevent Research Deputy of Shahrekord University of Medical production of B4 and D4 leukotrienes. On the other hand, Sciences; Shahrekord, Iran. release of prostaglandins and D4 leukotriene and COX1 inhibitors decrease tonic pain created like second phase References pain of formalin test and pain resulted from acetic acid. Lipooxigenase inhibitory role on release of prostaglandins Pain 6 and production of different B4 and D4 leukotrienes during [1] B onica JJ. The need of a . 1979; (3): 247-248. the second phase has been made clear to a large extent[127]. [2] R aj PP. Toxonomy and classification of pain. In: Kreitler S, Piper nigurm The handbook of chronic The most important compounds of fruit are Beltrutti D, Lamberto A, Niv D, editors. pain p-perrine and p-pyridine alkaloids. P-pyridine compound . New York: Nova Biomedical Books; 2007, p. 41-56. affects directly on opioid receptors[112]. Analgesic effect of [3] N asri H, Rafieian-Kopaei M. Protective effects of herbal Ziziphora tenuior J Res Med Sci 19 L. plant, belonging to Lamiaceae family, is antioxidants on diabetic kidney disease. 2014; (1): attributed to pulegone that seems perform through inhibiting 82-83. arachidonic acid and synthesis of prostaglandins and [4] B aradaran A, Madihi Y, Merrikhi A, Rafieian-Kopaei M, Nasri Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S50 2 H. Serum lipoprotein (a) in diabetic patients with various renal 2013; (2): 41-44. Pak J Med Sci 29 function not yet on dialysis. 2013; (Suppl 1): 354- [23] R abiei Z, Rafieian-Kopaei M, Mokhtari S, Alibabaei Z, Shahrani Lavandula 357. M. The effect of pretreatment with different doses of officinalis [5] B ehradmanesh S, Horestani MK, Baradaran A, Nasri H. ethanolic extract on memory, learning and nociception. Biomed Aging Pathol 4 Association of serum uric acid with proteinuria in type 2 diabetic 2014; (1): 71-76. J Res Med Sci 18 patients. 2013; (1): 44-46. [24] B have G, Karim F, Carlton SM, Gereau RW 4th. Peripheral group I [6] R afieian-Kopaei M, Ghobadi S, Nasri H. The protective effect metabotropic glutamate receptors modulate nociception in mice. Journal of Isfahan Nat Neurosci 4 of garlic extract on diabetic nephropathy. 2001; (4): 417-423. Medical School 31 2013; (248): 1267-1269. [25] G oudet C, Magnaghi V, Landry M, Nagy F, Gereau RW 4th, Pin JP. Brain [7] M agni G, Marchetti M, Moreschi C, Merskey H, Luchini SR. Metabotropic receptors for glutamate and GABA in pain. Res Rev 60 Chronic musculoskeletal pain and depressive symptoms in the 2009; (1): 43-56. National Health and Nutrition Examination. I. Epidemiologic [26] C arozzi V, Marmiroli P, Cavaletti G. Focus on the role of glutamate Pain 53 CNS Neurol follow-up study. 1993; (2): 163-168. in the pathology of the peripheral nervous system. ó Disord Drug Targets 7 [8] H uguet A, Mir J. The severity of chronic pediatric pain: an 2008; (4): 348-360. J Pain 9 Neuroscience: exploring the epidemiological study. 2008; (3): 226-236. [27] B ear MF, Connors BW, Paradiso MA. J brain [9] R afieian-Kopaei M. Medicinal plants and the human needs. . Philadelphia: Lippincott Williams and Wilkins; 2006, p. 411. HerbMed Plarmacol 1 Ciba 2012; (1): 1-2. [28] J essell TM. Substance P in nociceptive sensory neurons. Found Symp [10] S ewell RDE, Rafieian-Kopaei M. The history and ups and downs 1982; (91): 225-248. J HerbMed Pharmacol 3 of herbal medicine usage. 2014; (1): 1-3. [29] M uth-Selbach U, Hermanns H, Driehsen C, Lipfert P, Freynhagen J [11] N asri H, Shirzad H. and safety of medicinal plants. R. Racemic intrathecal mirtazapine but not its enantiomers acts HerbMed Plarmacol 2 Brain 2013; (2): 21-22. anti-neuropathic after chronic constriction injury in rats. Res Bull 79 [12] R afieian-Kopaei M, Baradaran A, Rafieian M. Plants antioxidants: 2009; (1): 63-68. J Nephropathol 2 from laboratory to clinic. 2013; (2): 152-153. [30] T hurmond RL, Gelfand EW, Dunford PJ. The role of histamine [13] K afash-Farkhad N, Asadi-Samani M, Rafieian-Kopaei M. A H1 and H4 receptors in allergic inflammation: the search for new Prangos Nat Rev Drug Discov 7 review on phytochemistry and pharmacological effects of antihistamines. 2008; (1): 41-53. ferulacea Life Sci J 10 Philos (L.) Lindl. 2013; (8s): 360-367. [31] M cMahon SB. NGF as a mediator of inflammatory pain. Trans R Soc Lond B Biol Sci 351 [14] N asri H, Rafieian-Kopaei M. Oxidative stress and aging 1996; (1338): 431-440. Int J Prev Med 4 prevention. 2013; (9): 1101-1102. [32] C huang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum [15] B aradaran A, Nasri H, Rafieian-Kopaei M. Oxidative stress AI, et al. Bradykinin and nerve growth factor release the capsaicin Nature and : possibility of hypertension therapy with receptor from PtdIns (4,5) P2-mediated inhibition. 2001; J Res Med Sci 19 411 antioxidants. 2014; (4): 358-367. (6840): 957-962. Proc Natl [16] R afieian-Kopaei M, Baradaran A, Rafieian M. Oxidative stress [33] S hu XQ, Mendell LM. Neurotrophins and hyperalgesia. J Res Med Sci Acad Sci U S A 96 and the paradoxical effects of antioxidants. 2013; 1999; (14): 7693-7696. 18 (7): 629. [34] C hen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, [17] M irhoseini M, Baradaran A, Rafieian-Kopaei M. Medicinal plants, Wood JN. A P2X purinoceptor expressed by a subset of sensory J HerbMed Pharmacol Nature 377 diabetes mellitus and urgent needs. 2013; neurons. 1995; (6548): 428-431. 2 (2): 53-54. [35] G iuffrida A, Beltramo M, Piomelli D. Mechanisms of J [18] S hirzad H, Taji F, Rafieian-Kopaei M. Correlation between endocannabinoid inactivation: biochemistry and pharmacology. Pharmacol Exp Ther 298 antioxidant activity of garlic extracts and WEHI-164 fibrosarcoma 2001; (1): 7-14. J Med Food 14 tumor growth in BALB/c mice. 2011; (9): 969-974. [36] W alker JM, Krey JF, Chu CJ, Huang SM. Endocannabinoids and Chem Phys [19] S hirzad H, Shahrani M, Rafieian-Kopaei M. Comparison of related fatty acid derivatives in pain modulation. Lipids 121 morphine and tramadol effects on phagocytic activity of mice 2002; (1-2): 159-172. in vivo Int Immunopharmacol 9 peritoneal phagocytes . 2009; (7-8): [37] S anger GJ. Endocannabinoids and the gastrointestinal tract: what Br J Pharmacol 152 968-970. are the key questions? 2007; (5): 663-670. Concise human [20] S ukkar MY, Ardawi MSM, El Munshid HA. [38] R afieian-Kopaei M, Sewell RDE. Morphine tolerance and SSRI physiology J Psychopharmacol 9 . New Jersey: Wiley-Blackwell Science; 2000, p. 446- antinocieeption. 1995; (3): A23-A91. 464. [39] R afieian-Kopaei M, Sewell RDE. Opioid tolerance and K ATP Analgesia 1 [21] S hirani M, Alibabaei Z, Kheiri S, Shirzad H, Taji F, Asgari A, et al. channel mediated antinociception. 1995; (4-6): 667- Euphorbia helioscopia Effect of extract on acute and chronic pain 670. JBUMS 13 in mice. 2011; (4): 14-18. [40] R afieian-Kopaei M, Sewell RDE. Chronic fluvoxamine does J [22] K iani MA, Khodadad A, Mohammadi S, Mobarhan MG, Saeidi M, not have any effect on opioid withdrawal place conditioning. ’ Psychophaemacol 8 Jafari SA, et al. Effect of peppermint on pediatrics pain under 1994; (148): A37. J HerbMed Pharmacol endoscopic examination of the large bowel. [41] R afieian-Kopaei M. Effects of antidepressants on morphine Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S51 Iran J Med Sci 23 withdrawal. 1998; (3-4): 120-125. [56] K arimi M, Parsaei P, Yazdan Asadi S, Ezzati S, Khadivi Boroujeni Camellia sinensis [42] R afieian-Kopaei M, Sewell RDE. Involvement of the serotonin R, Zamiri A, et al. Effects of ethanolic extract on Med J Islam Repub Iran system in SSRI-induced antinociception. histometric and histopathological healing process of burn wound 12 Middle East J Sci Res 13 1999; (4): 359-364. in rat. 2013; (1): 14-19. [43] E idi AH, Rustaiyan AH, Eidi M, Bahramian M. Antinociception [57] A sgary S, Keshvari M, Sahebkar A, Hashemi M, Rafieian-Kopaei Mentha piperita effects of ethanolic extract of leaves in adult male M. Clinical investigation of the acute effects of pomegranate Iran J Biol 23 mice. 2010; (4): 613-621. juice on blood pressure and endothelial function in hypertensive ARYA Atheroscler 9 [44] A libabaei Z, Pilehvarian A, Shirani M, Kheiri S, Taji F, Asgari individuals. 2013; (6): 326-331. Euphorbia helioscopia A, et al. Effect of on acetic acid-induced [58] A s g a r y S , S a h e b k a r A , A f s h a n i MR , K e s h v a r i M , J Shahrekord Univ Med abdominal constrictions in Balb/c mice. Haghjooyjavanmard S, Rafieian-Kopaei M. Clinical evaluation Sci 11 2010; (4): 9-14. of blood pressure lowering, endothelial function improving, [45] N asri S, Yousofvand N, Khani S. Effectiveness of exogen hypolipidemic and anti-inflammatory effects of pomegranate Phytother Res 28 testosterone and finasterid on morphine analgesia in male mices juice in hypertensive subjects. 2014; (2): 193-199. J Ilam Univ Med Sci 19 using formalin test. ; 2011; (2): 38-47. [59] N asri H, Rafieian-Kopaei M. Tubular kidney protection by Iran J Public Health 42 [46] B aradaran A, Madihi Y, Merrikhi A, Rafieian-Kopaei M, antioxidants. 2013; (10): 1194-1196. Nematbakhsh M, Asgari A, et al. Nephrotoxicity of hydroalcoholic [60] R afieian-Kopaei M, Beyki A, Nasri H. Antioxidant therapy in Teucrium polium Pak J Med Sci J Isfahan Med Sch 31 extract of in Wistar rats. 2013; hemodialysis patients. 2014; (261): 1897-1900. 29 (Suppl 1): 329-333. [61] B aradaran A, Nasri H, Nematbakhsh M, Rafieian-Kopaei M. [47] N asri H, Nematbakhsh M, Ghobadi S, Ansari R, Shahinfard N, Antioxidant activity and preventive effect of aqueous leaf extract Aloe vera Rafieian-Kopaei M. Preventive and curative effects of ginger of on gentamicin-induced nephrotoxicity in male Wistar Clin Ter 165 extract against histopathologic changes of gentamicin-induced rats. 2014; (1): 7-11. Int J Prev Med 4 tubular toxicity in rats. 2013; (3): 316-321. [62] S harafati chaleshtori R, Sharafati Chaleshtori F, Rafieian M. Juglans [48] A mini FG, Rafieian-Kopaei M, Nematbakhsh M, Baradaran A, Antibacterial effects of ethanolic extract of walnut leaves ( regia Propionibacterium acnes J Zanjan Univ Med Sci Health Nasri H. Ameliorative effects of metformin on renal histologic and ) on . Serv 18 biochemical alterations of gentamicin-induced renal toxicity in 2010; (71): 42-49. J Res Med Sci 17 Wistar rats. 2012; (7): 621-625. [63] R abiei Z, Rafieian-kopaei M, Heidarian E, Saghaei E, Mokhtari Zizyphus jujube [49] N asri H, Nematbakhsh M, Rafieian-Kopaei M. Ethanolic extract Sh. Effects of extract on memory and learning of garlic for attenuation of gentamicin-induced nephrotoxicity in impairment induced by bilateral electric lesions of the nucleus Iran J Kidney Dis 7 Neurochem Res 39 Wistar rats. 2013; (5): 376-382. basalis of Meynert in rat. 2014; (2): 353-360. [50] A sgary S, Kelishadi R, Rafieian-Kopaei M, Najafi S, Najafi [64] A sgary S, Rafieian-Kopaei M, Shamsi F, Najafi S, Sahebkar M, Sahebkar A. Investigation of the lipid-modifying and A. Biochemical and histopathological study of the anti- Cornus mas antiinflammatory effects of L. supplementation on hyperglycemic and anti-hyperlipidemic effects of cornelian Pediatr Cardiol Cornus mas J dyslipidemic children and adolescents. 2013; cherry ( L.) in alloxan-induced diabetic rats. 34 Complement Integr Med 11 (7): 1729-1735. 2014; (2): 63-69. [51] A sgary S, Rafieian-Kopaei M, Najafi S, Heidarian E, Sahebkar A. [65] A kbari F, Ansari-Samani R, Karimi A, Mortazaei S, Shahinfard N, Sesamum indicum Antihyperlipidemic effects of L. in rabbits fed Rafieian-Kopaei M. Effect of turnip on glucose and lipid profiles Sci World J Iran J Endocrinol Metab a high-fat diet. 2013; doi: 10.1155/2013/365892. of alloxan-induced diabetic rats. 2013; 14 [52] R afieian-Kopaei M, Asgary S, Adelnia A, Setorki M, Kajid K, (5): 492-497. Kazemi S, et al. The effects of cornelian cherry on atherosclerosis [66] R afieian-Kopaei M, Nasri H. Re: erythropoietin ameliorates J Med and atherogenic factors in hypercholesterolemic rabbits. oxidative stress and tissue injury following renal ischemia/ Plants Res 5 Med Princ Pract 23 2011; (13): 2670-2676. reperfusion in rat kidney and lung. 2014; (1): [53] S etorki M, Nazari B, Asgary S, Azadbakht L, Rafieian-Kopaei M. 95. Anti atherosclerotic effects of verjuice on hypocholesterolemic [67] N asri H, Tavakoli M, Ahmadi A, Baradaran A, Nematbakhsh M, Afr J Pharm Pharmacol 5 rabbits. 2011; (8): 1038-1045. Rafieian-Kopaei M. Ameliorative effect of melatonin against Pak J Med Sci [54] A sadi SY, Parsaei P, Karimi M, Ezzati S, Zamiri A, contrast media induced renal tubular cell injury. Camellia sinensis 30 Mohammadizadeh F, et al. Effect of green tea ( ) 2014; (2): 261-265. Int J Surg extract on healing process of surgical wounds in rat. [68] H osseini-asl K, Rafieian-kopaei M. Can patients with active 11 Am J Gastroenterol 97 2013; (4): 332-337. duodenal ulcer fast Ramadan? 2002; (9): [55] P arsaei P, Karimi M, Asadi SY, Rafieian-Kopaei M. Bioactive 2471-2472. Camellia sinensis components and preventive effect of green tea ( ) [69] S edighi M, Noori-Ahmadabadi M, Rafieian-Kopaei M, Int Rosa extract on post-laparotomy intra-abdominal adhesion in rats. Ebrahimpoor-Samani J, Shahinfard N. The effect of J Surg 11 damascena 2013; (9): 811-815. Mill hydro-alcoholic extract on the ileum contraction Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S52 J Mazandaran Univ Med Sci 23 Satureja hortensis in rat. 2014; (108): 29-39. effect of aqueous L. seed extract in male rat. Kelussia Physiol Pharmacol 8 [70] S edighi M, Rafieian-Kopaei M, Noori-Ahmadabadi M. 2005; (2): 163-168. odoratissima Mozaffarian inhibits ileum contractions through [85] A rzi A, Sarkaki A, Aghel N, Nazari Z, Zareii Naser abadi M. The Life Sci J Saliva officinalis voltage dependent and beta adrenergic receptors. 2012; effect of hydroalcoholic extract on analgesic 9 Sci Med J 10 (4): 1033-1038. effect of morphine in rat. 2011; (5): 505-513. [71] A khlaghi M, Shabanian G, Rafieian-Kopaei M, Parvin N, Saadat [86] N asri S, Ramezanghorbani A, Kamalinejad M. Analgesic and Stachys M, Akhlaghi M. Citrus aurantium blossom and preoperative anti-inflammatory effects of hydroalcoholic extract of Rev Bras Anestesiol 61 lavandulifolia vahl Armaghan anxiety. 2011; (6): 702-712. S, aerial parts in male mice. Danesh 16 [72] J afarzadeh L, Sedighi M, Behzadian M, Ansari-Samani R, 2011; (2): 161-171. Shahinfard N, Rafieian-Kopaei M. The teratogenic and [87] R oghani M, Baluchnejadmojarad T, Sabouri B, Nahavandi N. The Heracleum persicum abortifacient effects of hydroalcholic extract analgesic effect of oral administration of tarragon in diabetic rats. ’ J Qazvin Univ Med Sci 9 and its correlation with mothers estrogen and progesterone in 2006; (4): 19-24. JBUMS 16 Balb/C Mice. 2014; (3): 26-32. [88] V ahidi A, Dashti MH, Jamaladdini SH. Antinociceptive effect Sci J Shahid [73] H aj Hashemi VA, Ghanadi A, Mosavi D. Analgesic and of chamomill on formalin induced pain in rat. Sadoughi Univ Med Sci Health Ser 9 antiinflammatory effects of total extract, fraction and 2001; (2): 60-65. Salvia hydrangea J Res Med Sci 5 volatile oil of . 2000; (Suppl 2): [89] O ryan S, Nasri S, Amin G, Mohsen Kazemi-Mohammady SM. 10-14. Anti nociceptive and anti-inflammatory effects of aerial parts of Iavandula Gundelia tournefortii J Shahrekord Univ [74] H eidari MR, Zahedi MJ, Rezvani H. Analgesic effect of L. on NMRI male mice. officinalis Scientific- Med Sci 12 and histopatological studies in mice. 2011; (4): 8-15. Research Journal of Shahed University 8 2000; (30): 23-30. [90] D ashti Rahmatabadi MH, Anvari M, Rezai Sadrabadi M, Fallah Solanum melongena [75] F arshchi A, Ghiasi G, Abdollahuasl A. Antinociceptive and Tafti H, Zanbagh S, Yadegari S. The effect of Teucrium hyrcanicum antiinflammatory effects of aqueous extract L. hydro-alcoholic extract on chronic pain in male mice as Physiol Pharmacol 14 Iran J Med Aromat Plants 25 in male mice and rats. 2010; (1): 78-84. compared with morphine. 2009; (1): [76] T aherian AA, Rashidy-Pour A, Vafaei AA, Jarrahi M, Miladi- 129-138. Gorgi, Emami-Abarghoii M, et al. Assessment the effects of [91] K iasalari Z, Khalili M, Ashrafi M. Anti-nociceptive effect of Thymus vulgaris hydroalcoholic extract of on acute pain in hot alcoholic extract of henbane seed on the different phases of Koomesh 5 J Gorgan Uni Med Sci 11 plate and tail flick in mice. 2004; (3): 179-185. estrous cycle of female rats. 2010; (4): [77] M iladi Gorji H, Rashidi Pour A, Vafaei AA, Taherian AA. Opioid 1-7. receptors role on anti-nociceptive effects of the aqueous extracts [92] K halili Najafabadi M, Atyabi SM. Evaluation of analgesic effect of Melissa officinalis J Hormozgan Univ Med Sci Datura stramonium of in mice. 2006; seed extract in hot plate and formalin tested 10 Iran J Med Aromat Plants 20 (1): 23-28. on male rats. 2004; (3): 309-322. Solenanthus circinnatus [78] M okhtari M, Shariati M, Khodaparast L. The antinociceptive effect [93] R anjbar A. The analgesic effect of root Mentha pulegium J Isfahan Medica School 27 of hydro-alcoholic extract of leave in formalin extract in male rat. 2009; (101): 660-668. J Shahrekord Univ Med Sci 10 test in male rat. 2009; (4): 7-12. [94] H ejazian SH, Fatahi Bafghi A, Mahdavi SM. The analgesic effects Carum copticum [79] T aherian AA, Dehghanina M, Vafaei Aa, Sadeghi H, Miladi Gorgi of aqueous part of (L.) C. B. Clarke extract on Foeniculum vulgar Iran H. Effects of aqueous extract of fruit of on chronic pain and comparison with oil part of extract in mice. SJKU 12 J Med Aromat Plants 25 neurogenic and inflamatory pain in mice. 2007; (2): 29-36. 2009; (1): 104-112. [80] E idi A, Parivar K, Mazouji A, Akhtari Z. Antinociceptive effects [95] M okhtari M, Shariati M, Niknam H. The effect of antinociceptive Salvia hypoleuca Medical Sciences - J Rafsenjan Univ Med of essential oil of L. in mice. and anti inflammatory of hydro alcohols. Journal of Islamic Azad University, Tehran Medical Branch Sci 7 2006; 2008; (3): 165-172. 16 (3): 165-169. [96] E idi A, Eidi M, Badiei L. Antinociceptive effects of ethanolic Petroselinum crispum [81] G hahhari J, Vaezi G, Shariatifar N, Zendehdel Kh M. The study of extract of parsley ( L.) leaves in mice. Ziziphora tenuior Medical Sciences Journal of Islamic Azad University, Tehran hydroalcoholic extract of on visceral pain with Horizon Med Sci 15 Medical Branch 19 writhing test in mice. 2009; (3): 24-29. 2009; (3): 181-186. [82] S hahraki M, MirShekari H, Palan MJ. The comparison of [97] N asri S, Ramazani M, Yasa N. Antinociceptive and anti- Teucrium polium Apium nociceptive effect of and morphine in female inflammatory effects of hydro-alcoholic extract of Horizon Med Sci 12 graveolens J Shahrekord Univ Med Sci 10 rats. 2005; (1): 10-14. . 2009; (4): 25-31. [83] P ahlavan Y, Sepehri GR, Afarinesh Khaki MR, Sheibani V, Esmail [98] E brahimzadeh MA, Mahmoudi M, Saiednia S, Pourmorad F, Pour Bezenjani K, Pahlavan B. Intervention of morphine and Salimi E. Anti-inflammatory and anti-nociceptive properties Origanum vulgare Sambucus ebulus J naloxone on analgesic effects of extract in of fractionated extracts in different parts of . JAUMS 11 Mazandaran Univ Med Sci 16 male rat. 2011; (2): 134-142. 2006; (54): 35-47. [84] V erdi J, Sabetkasaie M, Sabet Kasaei M, Sharif SH. Analgesic [99] P arvardeh S, Niapoor M, Nassiri Asl M, Hosseinzadeh H. Mahmoud Bahmani et al./Asian Pac J Trop Med 2014; 7(Suppl 1): S43-S53 S53 Pistacia Antinocieptive, anti-inflammatory and toxicity effects of [114]R akhshandeh H, Vahdati-Mashhadian N, Dolati K, Hosseini M. vera J Med Plants 1 Rosa damascena J Biol Sci extracts in mice and rat. 2002; : 59-68. Antinociceptive effect of in mice. 8 [100]R amezani M, Amin G, Jalili E. Antinociceptive and anti- 2008; (1): 176-180. Vitex agnus inflammatory effects of hydroalcoholic extract of [115]M orteza-Semnani K, Saeedi M, Hamidian M, Vafamehr H, J Shahrekord Univ Med Sci 11 castus fruit in mice. 2010; (4): 46-51. Dehpour AR. Anti-inflammatory, analgesic activity and acute Glaucium grandiflorum J Ethnopharmacol [101]T aherian AA, Rashidy-Pour A, Vafaei AA, Jarrahi M, Miladi- toxicity of extract. 80 Gorgi H, Emami-Abarghooii M, et al. Effect of aqueous extract 2002; (2-3): 181-186. Coriandrum sativum of the seed on the reduction of acute and [116]H eidari MR, Asadipour A, Ghayoor M. Evaluation of analgesic J Rafsenjan Univ Med Sci 3 Matricaria chronic pain in mice. 2004; (4): 243- and ulcerogenic effect of methanolic extract of chamomilla J Qazvin Univ Med Sci 5 249. L. 2002; (4): 15-23. [102]P arvizpor AR, Ahmadiani A, Kamalinejad M. Possible role [117]H eshmatian B, Nasri S, Asghari Mehrabad J, Mahmoudi Far F. of serotonergic and opioid systems in analgesia induced by Lactuca sativa Trigonella foenum-graecum Antinociceptive effects of hydroalcoholic extract of ( ) longifolia Horizon Med Sci 16 administration of TFG leaves 2010 (2) 5 11 Iran J Physiol Pharmacol 4 leaves in male mice. ; : - . 2000 (1) 69 63 extract. ; : - . [118]H oodgar F, Nasri S, Amin G. Investigation of antinociceptive [103]H ajzadeh MR, Rakhshandeh H, Esmaeilizadeh M, Ghorbani A. Portolaca oleracea and anti-inflammatory effects of hydro-alcoholic extract of Securigera securidaca Horizon Med Sci 17 Analgesic and anti-inflammatory effects of ( ) Koomesh 5 L. 2010; 1 : 12-19. extracts in mice & rat. 2004; (3): 113-120. [119]H eidari MR, Najafi F, Asadi Pour A, Ansari M, Zahedi MJ, [104]A sadi Shekaari M, Sheibani V, Ebrahimi HA, Rismanchian M, Vahedian M. Analgesic and ulcerogenic effect of methanolic Kalantari Pour T, Afarinesh MR. Effect of long term consumption Melilotus officinalis J Kerman Univ Med Sci 8 extract of . 2001; (4): of aqueous date fruit extract on analgesia response in male rat. JBUMS 9 210-219. 2008; (6): 7-12. [120]M ohebali S, Nasri S, Kamalinejhad M, Noori AS. Antinociceptive [105]S adeghifard H, Zareian P. The study of analgesic effect of Berberis vulgaris ’ Artemisia herba alba & anti-inflammatory effects of L. root s hydroalcoholic extract of in acute and ’ SJKU 13 hydroalcoholic extract and determination of it s possible chronic models of pain in male rats. 2009; (4): 30-36. J Paramed Sci antinociceptive mechanism in male mice. 2011; [106]H ejazian SH. Evaluate the analgesic opiate receptors of hops 2 Humulus lupulus Iran J Med Aromat Plants (4): 12-18. ( L.) extract in mice. 23 [121]P arvin N, Ansari Samani R, Shahinfard N, Reissi S, Alibabaie Z, 2007; (2): 166-173. Tanacetum parthenium Asgari AA. Effect of alcoholic extract of [107]A rbabian S, Izadi HR, Ghoshooni H, Shams J, Zardooz H, J Qazvin Univ Med Sci 16 Crocus on acute pain in rat. 2012; (1): 15-21. Kamalinejad M, et al. Effect of water extract of saffron ( sativus [122]G olabi S, Hassaapour-ezati M, Rohampour K. Effect of aqueous ) on chronic phase of formaline test in female mice. Drosera spatulata Trauma Mon 14 extracts of sun-dew ( ) on the firing rate of PGi 2009; (01): 5-6. J Physiol nucleus neurons after formalin-induced pain in rats. [108]K halili M, Kiasalari Z, Farhadi E, Agah M. Effects of alcoholic Pharmacol 14 Zingiber officinalis 1389 (3) 287 282 extract of rhizome on acute and chronic ; : - . Koomesh 12 123 L LS P SS S LL F KA M BA inflammation and pain in rats. 2010; (2): 159-166. [ ] opes , ereira , ilva , igueiredo , oura , [109]V aez G, Tavasoli Z, Ranjbar-Bahadori S. Study on the different Almeida FR, et al. Antinociceptive effect of topiramate in models Elaeagnus angustifolia Life Sci dosages of aqueous extract with and of acute pain and diabetic neuropathy in rodents. 2009; Pejouhesh 84 without morphine on the antinociceptive rate in mice. (3-4): 105-110. 35 2011; (1): 27-33. [124]D ashti-Rahmatabadi MH, Vahidi Merjardi AR, Pilavaran AA, [110]H eidari MR, Vahedian M, Momenzadeh S, Hayatbakhsh-A MM, Farzan F. Antinociceptive effect of cinnamon extract on formalin Colchicum JSSU 17 Hayatbakhsh-A. Evaluation of the analgesic effect of induced pain in rat. 2009; (2): 190-199. szovitsii Fisch & C.A. Mey extract in mice: possible mechanism [125]S epehri GR, Sheibani V, Pahlavan Y, Afarinesh Khaki MR, Esmail J Rafsanjan Univ Med Sci 2 involved. 2005; (3 and 4): 187-194. Pour Bezenjani K, Pahlavan B. Effect of interacerebroventricular Origanum vulgare [111]Z areian P, Esmaeili Mahani S, Taherianfard M. The effect of injection of aqueous extract of L. ssp. viride J Med Fac J Ardabil Univ Med Sci 11 licorice root extract on acute and chronic pain. 2003; on pain threshold in male rats. 2011; (1): 10 : 851-857. 52-58. [112]Z akaria AZ, Patahuddin H, Monhamad AS, Israf DA, Sulaiman [126]M orshedi A, Dashti Rahmatabadi MH, Dehghan Harati M, In vivo Artemisia sieberi MR. anti-nociceptive and anti-inflammatory activities Bagherinasab MA, Salami AS. The effect of Piper sarmentosum J J Med of the aqueous extract of the leaves of . Besser. on inflammatory and neurogenic pain in mice. Ethnopharmacol 128 Plants 10 2010; (1): 42-48. 2011; (40): 48-57. [113]M okhtari M, Shariati M, Sadeghi N. Effect of extract from [127]K haksarian M, Javan M, Sonboli A, Motamedi F. Inhibition Juglans regia leaves on antinociceptive induced by morphine in of acute and chronic pain in male rats by aqueous extract of Tehran Islamic Azad Univ Med J 2 Hypericum perforatum Yafteh 5 formalin test. 2008; : 85-90. L. 2004; (3): 11-18.