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q-0 Pain Affect And Affect P Pain 1.Rainville . Brain Mechanisms of 5. Bourke CA , Carigan MJ , Dixon RJ . Upper Motor Pain Modulation. In Pain Current Opinion Neurobiology Neuron Effect s in Sheep Of Some Betacarboline 2002 ; 12 : 195 -204 . Alkaloid Iddentified In Zygophyllaceous Plants. Aust 2. Bahri L. Peganum Harmala L: A Poisonous Plant of Vet J 1990 ; 67: 248 -251 . North Africa. Vet Hum Toxicol 1991 ; 33 : 276 -277 . 3. Buckholtz N . Neurobiology of Tetrah ydro -ß- 6. Rommelspacher H , Bruning G , Susilo R , Nick M , Carbolines. Life Sci 1980 ; 27 : 893 -903 . Hill R . Pharmacology Of Harmane (1-Methyl -3,4 - Dihydrobetacarboline). Eur J Pharmacol 1985 ; 109 : 4. Wildmann J . Heterocycles as Physiological Ligands 363 -371 . For The Benzodiazepine Receptor And For Other 7. Breyer -Pfaff U, Waiter G , Stevens I , Gaertner HJ , Binding Sites. Pharmacol Res 1989 ; 21 : 673 -682 . Mundle G , Mann K . Elevated Norharman Plasma

6c j9k< ? ' / 23 .# / / ' / 0 ! e#$ ()* +& )1 ... ( Writhing )

Levels In Alcoholic Patients And Controls Resulting 21 . Hunskaar HS , Hole K . The Formalin Test In Mice: From Tobacco Smoking. Life Sci 1996 ; 58: 1425 - Dissociation Between Inflammatory And None - 1432 . Inflammatory Pain . Pain 1987 ; 30 : 103 -114 . 8.Tse YHS , Mak IT , Dickens BF . Antioxidative 22 . Tjolsen A . The Formalin Test: An Evaluation Of Properties of Harmane And Betacarboline Alkaloids. Method. Pain 1992 ; 51 : 5-17 . Biochem Pharmacol 1991 ; 42 : 459 -464 . 23 . Shibata M. Modified Formalin Test: Charectristic 9.Taylor SG , Little HJ , Nutt DJ , Sellars NA . A Biphasic Pain Response. Pain 1989 ; 38 : 346 -352 . Benzodiazepine Agonist And Contragonist Have 24 .Charney DS , Mihic SJ , Harris RA . Hypnotics And Hypothermic Effects In Rodents. Neuropharmacol Sedatives .In : Brunton LL , Lazo JS , Parker KL . 1985 ; 24 : 69- 73 . (Editors ). Goodman and Gilman's The Pharmacological 10 .Ariciogl u-Kartal F , Kayir H , Uzbay IT . Effects of Basis of Therapeuti cs . 11 th Ed. New York , Mc Graw Harman And Harmine On Naloxone -Precipitated Hill 200 6: 401 -427 . Withdrawal Syndrom In Morphine -Dependent Rats. 25 . Korpi ER , Grunder G , Luddens H . Drug Intraction Life Sci 2003 ; 73 : 2363 -2371 . At GABA -A Receptors. Prog Neurobiol 2002 ; 67 : 113 - 11 .Airaksinen MM . Binding Of Beta -Carbolines And 159 . Tetrahydroisoquinolines Bye Opiate Recepto rs Of The Delta Type . Pharmacol Toxicol 1984 ; 55 : 380 -385 . 26 . Smith GB ,Olsen WR . Functional Domains of GABA -A Receptors. Trends Pharmacol Sci 1995 ; 16 : 12 .Dhara V , Suba T , Sen T. Preliminary Studies On 162 -168 . The Antiinflammatory And Analgesic Activity Of Methanolic Fraction Of The Root Extract Of Tragia 27 . Hafely WE . Pharmacology of The Allosteric Invulocrate . J Ethnopharmacol 2000 ; 72 : 265 -268 . Modulation Of GABA -A Receptors By BZD -Receptor Ligands. In : Barnard EA , Costa E . Allosteric 13 .Reibero RA . Involvement Of Resident Modulation Of Aminoacid Receptors: Therapeutic Macrophages And Mastcells In Writhing Nociception Implications . Newyork ; Raven Press 1989 : 47- 69 . Response Induced By Zymosan And Acetic Acid. Eur J Pharmacol 2000 ; 387 : 307 -313 . 28 .Mehta AK Ticku MK . An Update On GABA -A 14 . Gary JB . Animal Models Of Pain . In : Kruger L . Receptors. Brain Res Rev 1999 ; 29 : 196 -217 . Methods In Pain Research . New York , CR C Press , 2001 : 378 -425 . 29 . Cowen PJ , Green AR , Nutt DJ . Ethyl Beta - 15 . Farzin D , Mansouri N . Antidepressant -Like Effect Caboline Carboxylate Lowes Seizure Thershold an d Of Harmane And Other Β -Carbolines In The Mouse Antagonizes Flurazepam -Induced Sedation In Rats. Forced Swim Test. Eur Neur psycho pharmacol 2006 ; Nature 1981 ; 290 : 54 -55 . 16 : 324 -328 . 30 . Prado De Carvalh o L , Greeksch G , Cavalheiro EA . 16 .Hof fman EJ , Warren EW . Flumazenil : A Characterization Of Convultion Induced by Methyl Benzodiazepine Antagonist. Clin Pharmcol 1993 ; 12 : Beta -Carboline -3-Carboxylate in Mice. Eur . J. 641 -656 . Pharmacol 1984 ; 103 : 287 -293 . 17 . Farzin D , Attarzedeh M . Influence of Different 31 . Venault P , Chapoutheir G , Simiand J . Histamine Receptor Agonists on Apomorphine - Enhancement Of Performance By Methyl Beta - Induced Licking Behavior in Rat. Eur J Pharmacol Carboline -3-Carb oxylate, In Learning and Memory 2000 ; 404 : 169 -174 . Tasks. Brain Res Bull 1987 ; 19: 365 -370 . 32 . Sieve AN . Pain and Negative Affect: Evidence The 18 .Fanselow MS , Kim JJ . The Benzodiazepine Inverse Inverse Benzodiazepine Agonist DMCM Inhibits Pain Agonist DM CM as an Unconditional Stimulus for and Learning In Rats. Psychopharmacol 2001 ; 153 : Fear -Induced Analgesia: Implication For The Role of 180 -190 . GABA -A Receptors In Fear -Related Behavior. Behav . 33 . Fanselow MS , Baack es MP . Conditioning Fear - Neurosci 1992 ; 106 : 336 -344 . Induced Opiate Analgesia on The Formalin Test: 19 . Maie r SF , Busch CR, Maswood RE , Watkins LR . Evidence for Two Adversive Motivational Systems. The Dorsal Raphe Nucleus Is A Site Of Act ion Learn . Motiv 1982 ; 13 : 200 -221 . Mediatingthe Behavioral Effects of The 34 . Chance WT . Autoanalgesia : Behaviorally Benzodiazepine Receptor Inverse Agonist DMCM . Activated Antinociception. Eur J Pharmacol 1977 ; 44 : Behav Neuro sci 1995 ; 109 : 759 -766 . 283 -284 . 20 . Farouk L. Evaluation Of The Analgesic Effect Of 35 . Watkins LR , Cobelli DA , Mayer DJ . Classical Alkaloid Extract Of Peganum Hamala L.: Possible Conditioning of Front Paw and Hind Paw Footshock Mechanisms Involved. J Ethnopharm acol 2008 ; 115 : Induced Analgesia: Naloxone Reversibility and 445 -449 . Descending Pathways. Brain Res 1982 ; 243 : 119 -132 .

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*Farzin D. (Ph D) 1- Mousavi E. (M D)1 *Corresponding Address: Department of Pharmacology, Faculty of Medicine, Mazandaran University of Med ical Sciences, Sari, IRAN E-mail: [email protected] Received: 31/ May /2010 Accepted: 9/oct /2010 Abstract Introduction: The β-carbolines harmane, harmine and norharmane are the members of Harmala ,s al kaloids group (Peganum harmala, Zygophillaceae). The β-carboline alkaloids adjoined to benzodiazepine site of the γ -aminobutyric acid type A (GABA A). These alkaloids also inhibit ed cyclooxygenase and lipoxygenase activities. These findings showed that the β-carbolines should be able to reduce writhing nociceptio induced by acetic acid - in mice. Objective: To assess the effects of acute treatment with harmane, norharmane and harmine on the writhing induced by acetic acid in mice. Materials and Methods: The experiments were carried out on male BALB /C mice (20 -25 g). Intraperiton eal ( I.p) injection of acetic acid (0.6% ) was performed in order to cause writhing behavior. This behavior was recorded by direct observation for a 30-minutes period. Decrease of writhi ng count is indicative of an anti -noc iception . In order to avoid the possibility of a physicochemical interaction between them , Drugs were administered on opposite sides of peritoned. Results: Intraperitoneal ( I.p ) injection of Harman e ( 5-20 mg /kg ) on 6-9 m ice, norharman e ( 5-15 mg /kg ) on 8-9 mice and harmine (10 -15mg /kg ) on 8-9 mice in per group decreased the writhing behavior significantly (P<0.0001 , P<0.0003 and P<0.0016 , respectively ). The inhibitory effects of the mentioned drugs were antagonized by fluma zenil (2 mg /kg ) Conclusion : Effects of harmane, norharmane and harmine on writhing response may be mediated through an inverse agonistic mechanism located in the benzodiazepine receptors.

Key words: Pain / Carbolin s/ Harmine / Mouse ______Journal of Guilan University of Medical Sciences , No : 76, Pages: 29 -37

1. Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, IRAN j9k< ? ' / 23 .# / / ' / 0 ! e#$ ()* +& )1 6f