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Effects of Monoamine Reuptake Inhibitors in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Rats

Published:January 18, 2013DOI:https://doi.org/10.1016/j.jpain.2012.11.006

      Abstract

      Pain is associated with stimulation of some behaviors (eg, withdrawal reflexes) but depression of many other behaviors (eg, feeding, locomotion, positively reinforced operant behavior). Drugs that block reuptake of serotonin, norepinephrine, and/or dopamine are widely used to treat depression, and they have also emerged as useful drugs for treatment of pain. This study compared effects of selective and mixed-action inhibitors of serotonin, norepinephrine, and/or dopamine reuptake in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute acid served as a noxious stimulus to stimulate a writhing response or depress intracranial self-stimulation (ICSS) in Sprague Dawley rats. Selective reuptake inhibitors of serotonin (citalopram, clomipramine) and norepinephrine (nisoxetine, nortriptyline) and a mixed-action reuptake inhibitor of serotonin and norepinephrine (milnacipran) blocked acid-stimulated writhing but failed to block acid-induced depression of ICSS. Selective dopamine reuptake inhibitors (RTI-113 [3ß-(4-chlorophenyl)tropane-2ß-carboxylic acid phenyl ester hydrochloride], bupropion) and a triple reuptake inhibitor of dopamine, serotonin, and norepinephrine (RTI-112 [3ß-(3-methyl-4-chlorophenyl)tropane-2ß-carboxylic acid methyl ester hydrochloride]) blocked both acid-stimulated writhing and acid-induced depression of ICSS, although these drugs also produced an abuse-related facilitation of ICSS in the absence of the noxious stimulus. These results support further consideration of dopamine reuptake inhibitors as candidate analgesics, although abuse liability remains a concern.

      Perspective

      Monoamine reuptake inhibitors are used to treat depression and some forms of pain. This study examined effects of monoamine reuptake inhibitors in a preclinical assay of pain-related behavioral depression. The results support further consideration of dopamine reuptake inhibitors as candidate analgesics under selected circumstances, although abuse liability remains a concern.

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      References

        • Altier N.
        • Stewart J.
        The role of dopamine in the nucleus accumbens in analgesia.
        Life Sci. 1999; 65: 2269-2287
        • Aoki M.
        • Tsuji M.
        • Takeda H.
        • Harada Y.
        • Nohara J.
        • Matsumiya T.
        • Chiba H.
        Antidepressants enhance the antinociceptive effects of carbamazepine in the acetic acid-induced writhing test in mice.
        Eur J Pharmacol. 2006; 550: 78-83
        • Ardid D.
        • Marty H.
        • Fialip J.
        • Privat A.M.
        • Eschalier A.
        • Lavarenne J.
        Comparative effects of different uptake inhibitor antidepressants in two pain tests in mice.
        Fundam Clin Pharmacol. 1992; 6: 75-82
        • Bair M.J.
        • Wu J.
        • Damush T.M.
        • Sutherland J.M.
        • Kroenke K.
        Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients.
        Psychosom Med. 2008; 70: 890-897
        • Bardin L.
        • Gregoire S.
        • Aliaga M.
        • Malfetes N.
        • Vitton O.
        • Ladure P.
        • Newman-Tancredi A.
        • Depoortere R.
        Comparison of milnacipran, duloxetine and pregabalin in the formalin pain test and in a model of stress-induced ultrasonic vocalizations in rats.
        Neurosci Res. 2010; 66: 135-140
        • Basile A.S.
        • Janowsky A.
        • Golembiowska K.
        • Kowalska M.
        • Tam E.
        • Benveniste M.
        • Popik P.
        • Nikiforuk A.
        • Krawczyk M.
        • Nowak G.
        • Krieter P.A.
        • Lippa A.S.
        • Skolnick P.
        • Koustova E.
        Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain.
        J Pharmacol Exp Ther. 2007; 321: 1208-1225
        • Berrocoso E.
        • Mico J.A.
        • Vitton O.
        • Ladure P.
        • Newman-Tancredi A.
        • Depoortere R.
        • Bardin L.
        Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain.
        Eur J Pharmacol. 2011; 655: 46-51
        • Bomholt S.F.
        • Mikkelsen J.D.
        • Blackburn-Munro G.
        Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain.
        Neuropharmacology. 2005; 48: 252-263
        • Borsook D.
        • Becerra L.
        • Carlezon Jr., W.A.
        • Shaw M.
        • Renshaw P.
        • Elman I.
        • Levine J.
        Reward-aversion circuitry in analgesia and pain: implications for psychiatric disorders.
        Eur J Pain. 2007; 11: 7-20
        • Carlezon Jr., W.A.
        • Beguin C.
        • DiNieri J.A.
        • Baumann M.H.
        • Richards M.R.
        • Todtenkopf M.S.
        • Rothman R.B.
        • Ma Z.
        • Lee D.Y.
        • Cohen B.M.
        Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
        J Pharmacol Exp Ther. 2006; 316: 440-447
        • Carlezon Jr., W.A.
        • Chartoff E.H.
        Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation.
        Nat Protoc. 2007; 2: 2987-2995
        • Cheetham S.C.
        • Viggers J.A.
        • Butler S.A.
        • Prow M.R.
        • Heal D.J.
        [3H]nisoxetine–a radioligand for noradrenaline reuptake sites: Correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments.
        Neuropharmacology. 1996; 35: 63-70
        • Cheetham S.C.
        • Viggers J.A.
        • Slater N.A.
        • Heal D.J.
        • Buckett W.R.
        [3H]paroxetine binding in rat frontal cortex strongly correlates with [3H]5-HT uptake: Effect of administration of various antidepressant treatments.
        Neuropharmacology. 1993; 32: 737-743
        • Cobos E.J.
        • Ghasemlou N.
        • Araldi D.
        • Segal D.
        • Duong K.
        • Woolf C.J.
        Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia.
        Pain. 2012; 153: 876-884
        • Cook C.D.
        • Carroll I.F.
        • Beardsley P.M.
        Cocaine-like discriminative stimulus effects of novel cocaine and 3-phenyltropane analogs in the rat.
        Psychopharmacology (Berl). 2001; 159: 58-63
        • Detke M.J.
        • Johnson J.
        • Lucki I.
        Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.
        Exp Clin Psychopharmacol. 1997; 5: 107-112
        • Duarte I.D.
        • Nakamura M.
        • Ferreira S.H.
        Participation of the sympathetic system in acetic acid-induced writhing in mice.
        Braz J Med Biol Res. 1988; 21: 341-343
        • Dworkin R.H.
        • Turk D.C.
        • Farrar J.T.
        • Haythornthwaite J.A.
        • Jensen M.P.
        • Katz N.P.
        • Kerns R.D.
        • Stucki G.
        • Allen R.R.
        • Bellamy N.
        • Carr D.B.
        • Chandler J.
        • Cowan P.
        • Dionne R.
        • Galer B.S.
        • Hertz S.
        • Jadad A.R.
        • Kramer L.D.
        • Manning D.C.
        • Martin S.
        • McCormick C.G.
        • McDermott M.P.
        • McGrath P.
        • Quessy S.
        • Rappaport B.A.
        • Robbins W.
        • Robinson J.P.
        • Rothman M.
        • Royal M.A.
        • Simon L.
        • Stauffer J.W.
        • Stein W.
        • Tollett J.
        • Wernicke J.
        • Witter J.
        Core outcome measures for chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2005; 113: 9-19
        • Enggaard T.P.
        • Klitgaard N.A.
        • Gram L.F.
        • Arendt-Nielsen L.
        • Sindrup S.H.
        Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans.
        Clin Pharmacol Ther. 2001; 69: 245-251
        • Enggaard T.P.
        • Poulsen L.
        • Arendt-Nielsen L.
        • Hansen S.H.
        • Bjornsdottir I.
        • Gram L.F.
        • Sindrup S.H.
        The analgesic effect of codeine as compared to imipramine in different human experimental pain models.
        Pain. 2001; 92: 277-282
        • Fields H.L.
        • Basbaum A.I.
        • Heinricher M.M.
        Central nervous system mechanisms of pain modulation.
        in: McMahon L.R. Koltzenburg M. Textbook of Pain. Elsevier, London, UK2006: 125-142
        • Goldenberg D.L.
        Pain/Depression dyad: A key to a better understanding and treatment of functional somatic syndromes.
        Am J Med. 2010; 123: 675-682
        • Gordon N.C.
        • Heller P.H.
        • Gear R.W.
        • Levine J.D.
        Interactions between fluoxetine and opiate analgesia for postoperative dental pain.
        Pain. 1994; 58: 85-88
        • Hall F.S.
        • Schwarzbaum J.M.
        • Perona M.T.
        • Templin J.S.
        • Caron M.G.
        • Lesch K.P.
        • Murphy D.L.
        • Uhl G.R.
        A greater role for the norepinephrine transporter than the serotonin transporter in murine nociception.
        Neuroscience. 2011; 175: 315-327
        • Hall F.S.
        • Stellar J.R.
        • Kelley A.E.
        Acute and chronic desipramine treatment effects on rewarding electrical stimulation of the lateral hypothalamus.
        Pharmacol Biochem Behav. 1990; 37: 277-281
        • Hauser W.
        • Petzke F.
        • Uceyler N.
        • Sommer C.
        Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: A systematic review with meta-analysis.
        Rheumatology (Oxford). 2010; 50: 532-543
        • Hauser W.
        • Wolfe F.
        • Tolle T.
        • Uceyler N.
        • Sommer C.
        The role of antidepressants in the management of fibromyalgia syndrome: A systematic review and meta-analysis.
        CNS Drugs. 2012; 26: 297-307
        • Hendershot L.C.
        • Forsaith J.
        Antagonism of the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and nonanalgesics.
        J Pharmacol Exp Ther. 1959; 125: 237-240
        • Institute of Medicine
        Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.
        The National Academies Press, Washington, DC2011
        • Iversen L.
        Neurotransmitter transporters and their impact on the development of psychopharmacology.
        Br J Pharmacol. 2006; 147: S82-S88
        • Iyengar S.
        • Webster A.A.
        • Hemrick-Luecke S.K.
        • Xu J.Y.
        • Simmons R.M.
        Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.
        J Pharmacol Exp Ther. 2004; 311: 576-584
        • Jarcho J.M.
        • Mayer E.A.
        • Jiang Z.K.
        • Feier N.A.
        • London E.D.
        Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction.
        Pain. 2012; 153: 744-754
        • Kuhar M.J.
        • McGirr K.M.
        • Hunter R.G.
        • Lambert P.D.
        • Garrett B.E.
        • Carroll F.I.
        Studies of selected phenyltropanes at monoamine transporters.
        Drug Alcohol Depend. 1999; 56: 9-15
        • Kula N.S.
        • Baldessarini R.J.
        • Tarazi F.I.
        • Fisser R.
        • Wang S.
        • Trometer J.
        • Neumeyer J.L.
        [3H]beta-CIT: A radioligand for dopamine transporters in rat brain tissue.
        Eur J Pharmacol. 1999; 385: 291-294
        • Kwilasz A.J.
        • Negus S.S.
        Dissociable effects of the cannabinoid receptor agonists Δ9-tetrahydrocannabinol and CP55940 on pain-stimulated vs. pain-depressed behavior in rats.
        J Pharmacol Exp Ther. August 14, 2012; (Epub ahead of print)
        • Lee K.
        • Kornetsky C.
        Acute and chronic fluoxetine treatment decreases the sensitivity of rats to rewarding brain stimulation.
        Pharmacol Biochem Behav. 1998; 60: 539-544
        • Letchworth S.R.
        • Smith H.R.
        • Porrino L.J.
        • Bennett B.A.
        • Davies H.M.
        • Sexton T.
        • Childers S.R.
        Characterization of a tropane radioligand, [(3)H]2beta-propanoyl-3beta-(4-tolyl) tropane ([(3)H]PTT), for dopamine transport sites in rat brain.
        J Pharmacol Exp Ther. 2000; 293: 686-696
        • Leventhal L.
        • Smith V.
        • Hornby G.
        • Andree T.H.
        • Brandt M.R.
        • Rogers K.E.
        Differential and synergistic effects of selective norepinephrine and serotonin reuptake inhibitors in rodent models of pain.
        J Pharmacol Exp Ther. 2007; 320: 1178-1185
        • Marston H.M.
        • Martin F.D.
        • Papp M.
        • Gold L.
        • Wong E.H.
        • Shahid M.
        Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation.
        J Psychopharmacol. 2010; 25: 1388-1398
        • Martin T.J.
        • Buechler N.L.
        • Kahn W.
        • Crews J.C.
        • Eisenach J.C.
        Effects of laparotomy on spontaneous exploratory activity and conditioned operant responding in the rat: a model for postoperative pain.
        Anesthesiology. 2004; 101: 191-203
        • Matson D.J.
        • Broom D.C.
        • Carson S.R.
        • Baldassari J.
        • Kehne J.
        • Cortright D.N.
        Inflammation-induced reduction of spontaneous activity by adjuvant: A novel model to study the effect of analgesics in rats.
        J Pharmacol Exp Ther. 2007; 320: 194-201
        • Mico J.A.
        • Ardid D.
        • Berrocoso E.
        • Eschalier A.
        Antidepressants and pain.
        Trends Pharmacol Sci. 2006; 27: 348-354
        • Millan M.J.
        • Gobert A.
        • Lejeune F.
        • Newman-Tancredi A.
        • Rivet J.M.
        • Auclair A.
        • Peglion J.L.
        S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine.
        J Pharmacol Exp Ther. 2001; 298: 565-580
        • Mochizucki D.
        Serotonin and noradrenaline reuptake inhibitors in animal models of pain.
        Hum Psychopharmacol. 2004; 19: S15-S19
        • Mochizuki D.
        • Tsujita R.
        • Yamada S.
        • Kawasaki K.
        • Otsuka Y.
        • Hashimoto S.
        • Hattori T.
        • Kitamura Y.
        • Miki N.
        Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats.
        Psychopharmacology (Berl). 2002; 162: 323-332
        • Mogil J.S.
        • Wilson S.G.
        • Wan Y.
        Assessing nociception in murine subjects.
        in: Kruger L. Methods in Pain Research. CRC Press, Boca Raton, FL2001: 11-39
        • National Research Council
        Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research.
        National Academies Press, Washington, DC2003
        • Negus S.S.
        • Bilsky E.J.
        • Pereira Do Carmo G.
        • Stevenson G.W.
        Rationale and methods for assessment of pain-depressed behavior in preclinical assays of pain and analgesia.
        in: Szallasi A. Methods in Molecular Biology: Analgesia. Humana Press, New York, NY2010: 79-91
        • Negus S.S.
        • Morrissey E.M.
        • Rosenberg M.
        • Cheng K.
        • Rice K.C.
        Effects of kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats.
        Psychopharmacology (Berl). 2010; 210: 149-159
        • Negus S.S.
        • O’Connell R.
        • Morrissey E.
        • Cheng K.
        • Rice K.C.
        Effects of peripherally restricted kappa opioid receptor agonists on pain-related stimulation and depression of behavior in rats.
        J Pharmacol Exp Ther. 2012; 340: 501-509
        • Negus S.S.
        • Rosenberg M.B.
        • Altarifi A.A.
        • O’Connell R.H.
        • Folk J.E.
        • Rice K.C.
        Effects of the delta opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats.
        J Pain. 2012; 13: 317-327
        • Negus S.S.
        • Vanderah T.W.
        • Brandt M.R.
        • Bilsky E.J.
        • Becerra L.
        • Borsook D.
        Preclinical assessment of candidate analgesic drugs: recent advances and future challenges.
        J Pharmacol Exp Ther. 2006; 319: 507-514
        • Nicholson K.L.
        • Balster R.L.
        • Golembiowska K.
        • Kowalska M.
        • Tizzano J.P.
        • Skolnick P.
        • Basile A.S.
        Preclinical evaluation of the abuse potential of the analgesic bicifadine.
        J Pharmacol Exp Ther. 2009; 330: 236-248
        • Otsuka N.
        • Kiuchi Y.
        • Yokogawa F.
        • Masuda Y.
        • Oguchi K.
        • Hosoyamada A.
        Antinociceptive efficacy of antidepressants: assessment of five antidepressants and four monoamine receptors in rats.
        J Anesth. 2001; 15: 154-158
        • Paul I.A.
        • Duncan G.E.
        • Kuhn C.
        • Mueller R.A.
        • Hong J.S.
        • Breese G.R.
        Neural adaptation in imipramine-treated rats processed in forced swim test: assessment of time course, handling, rat strain and amine uptake.
        J Pharmacol Exp Ther. 1990; 252: 997-1005
        • Pedersen L.H.
        • Nielsen A.N.
        • Blackburn-Munro G.
        Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain.
        Psychopharmacology (Berl). 2005; 182: 551-561
        • Pelissier T.
        • Hernandez A.
        • Mestre C.
        • Eschalier A.
        • Laurido C.
        • Paeile C.
        • Alvarez P.
        • Soto-Moyano R.
        Antinociceptive effect of clomipramine in monoarthritic rats as revealed by the paw pressure test and the C-fiber-evoked reflex.
        Eur J Pharmacol. 2001; 416: 51-57
        • Pereira Do Carmo G.
        • Stevenson G.W.
        • Carlezon W.A.
        • Negus S.S.
        Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior.
        Pain. 2009; 144: 170-177
        • Ren K.
        • Dubner R.
        Descending modulation in persistent pain: an update.
        Pain. 2002; 100: 1-6
        • Richards B.L.
        • Whittle S.L.
        • Buchbinder R.
        Antidepressants for pain management in rheumatoid arthritis.
        Cochrane Database Syst Rev. 2011; : CD008920
        • Ritz M.C.
        • Lamb R.J.
        • Goldberg S.R.
        • Kuhar M.J.
        Cocaine receptors on dopamine transporters are related to self-administration of cocaine.
        Science. 1987; 237: 1219-1223
        • Rojas-Corrales M.O.
        • Casas J.
        • Moreno-Brea M.R.
        • Gibert-Rahola J.
        • Mico J.A.
        Antinociceptive effects of tricyclic antidepressants and their noradrenergic metabolites.
        Eur Neuropsychopharmacol. 2003; 13: 355-363
        • Sanchez C.
        • Hyttel J.
        Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding.
        Cell Mol Neurobiol. 1999; 19: 467-489
        • Sawynok J.
        • Esser M.J.
        • Reid A.R.
        Antidepressants as analgesics: An overview of central and peripheral mechanisms of action.
        J Psychiatry Neurosci. 2001; 26: 21-29
        • Tracey I.
        Getting the pain you expect: Mechanisms of placebo, nocebo and reappraisal effects in humans.
        Nat Med. 2010; 16: 1277-1283
        • Veizi I.E.
        • Chelimsky T.C.
        • Janata J.W.
        Chronic regional pain syndrome: What specialized rehabilitation services do patients require?.
        Curr Pain Headache Rep. 2012; 16: 139-146
        • Villemure C.
        • Laferriere A.C.
        • Bushnell M.C.
        The ventral striatum is implicated in the analgesic effect of mood changes.
        Pain Res Manag. 2012; 17: 69-74
        • Vlachou S.
        • Markou A.
        Intracranial self-stimulation, Neuromethods Vol. 53.
        in: Olmstead M. Animal Models of Drug Addiction. Humana Press, New York, NY2011: 3-56
        • Wallace M.S.
        • Barger D.
        • Schulteis G.
        The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: A double-blinded, placebo-controlled, crossover study.
        Anesth Analg. 2002; 95: 973-978
        • Wang R.I.
        • Johnson R.P.
        • Lee J.C.
        • Waite E.M.
        The oral analgesic efficacy of bicifadine hydrochloride in postoperative pain.
        J Clin Pharmacol. 1982; 22: 160-164
        • Watson C.P.N.
        • Chipman M.L.
        • Monks R.C.
        Antidepressant analgesics: a systematic review and comparative study.
        in: McMahon L.R. Koltzenburg M. Textbook of Pain. Elsevier, London, UK2006: 481-497
        • Webb S.S.
        • Smith G.M.
        • Evans W.O.
        • Webb N.C.
        Toward the development of a potent, nonsedating, oral analgesic.
        Psychopharmacology (Berl). 1978; 60: 25-28
        • Wood P.B.
        Role of central dopamine in pain and analgesia.
        Expert Rev Neurother. 2008; 8: 781-797
        • Yang J.C.
        • Clark W.C.
        • Dooley J.C.
        • Mignogna F.V.
        Effect of intranasal cocaine on experimental pain in man.
        Anesth Analg. 1982; 61: 358-361
        • Yokogawa F.
        • Kiuchi Y.
        • Ishikawa Y.
        • Otsuka N.
        • Masuda Y.
        • Oguchi K.
        • Hosoyamada A.
        An investigation of monoamine receptors involved in antinociceptive effects of antidepressants.
        Anesth Analg. 2002; 95: 163-168
        • Younger J.
        • Aron A.
        • Parke S.
        • Chatterjee N.
        • Mackey S.
        Viewing pictures of a romantic partner reduces experimental pain: Involvement of neural reward systems.
        PLoS One. 2010; 5: e13309