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Antinociceptive effect of bupropion on visceral pain and its mechanism of action

Year 2024, Volume: 49 Issue: 2, 415 - 423, 30.06.2024
https://doi.org/10.17826/cumj.1429753

Abstract

PPurpose: Bupropion is an antidepressant that inhibits noradrenaline and dopamine reuptake. In the current scientific literature, there is limited information regarding the effects of bupropion on pain, predominantly derived from somatic pain studies. This study aims to investigate the impact of bupropion for the first time in visceral pain induced by colorectal distension, a pure visceral pain model, and to reveal the role of various receptors involved in pain control in this effect.
Materials and Methods: Male Sprague-Dawley rats were used in the study. Visceral pain was assessed by colorectal distension-induced visceromotor response. Bupropion is administered gastrically at 5, 10, 20, and 40 mg/kg doses. The mechanism of action of bupropion at the spinal cord level was investigated by intrathecal administration of antagonists of α1 and α2 adrenoceptors (prazosin and yohimbine), D1 and D2 dopamine (SCH 23390 and sulpiride) and opioid receptors (naloxone) 10 minutes before bupropion’s effective dose.
Results: Bupropion showed significant antinociceptive effects at 20 and 40 mg/kg intragastric doses; no difference was found between these two doses. Intrathecally administered yohimbine (30 µg/rats), sulpiride (30 µg/rats, i.t.), and naloxone (2.5 µg/rats) diminished the antinociceptive effect of bupropion. Prazosin and SCH 23390 did not alter bupropion’s effect.
Conclusion: The findings show the antinociceptive effect of bupropion in visceral pain, and adrenergic, dopaminergic, and opioidergic receptors in the spinal cord play a role in this effect.

Ethical Statement

This study was approved by Ondokuz Mayis University Animal Experiments Ethics Committee with the acceptance number 2020/25 on 14/07/2020.

Supporting Institution

Ondokuz Mayıs University BAP

Project Number

PYO.TIP.1904.20.012

References

  • Mico J, Ardid D, Berrocoso E, Eschlier A. Antidepressants and pain. Trends Pharmacol Sci. 2006;27:348–54.
  • Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017;18:2483.
  • Hajhashemi V, Minaiyan M, Banafshe HR, Mesdaghinia A, Abed A. The anti-inflammatory effects of venlafaxine in the rat model of carrageenan-induced paw edema. Iran J Basic Med Sci. 2015;18:654–8.
  • Schwartz ES, Gebhart GF. Visceral pain. In Behavioral Neurobiology of Chronic Pain (Eds BK Taylor, DP Finn): 171-97. Berlin, Springer. 2014.
  • Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry. 2004;06:159–66.
  • Hajhashemi V, Khanjani P. Analgesic and anti-inflammatory activities of bupropion in animal models. Res Pharm Sci. 2014;9:251–7.
  • Marinho BG, Miranda LS, da S Costa J, Leitão SG, Vasconcellos ML, Pereira VL et al. The antinociceptive properties of the novel compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one in acute pain in mice. Behav Pharmacol. 2013;24:10-9.
  • Isguzar O, Baris S, Bozkurt A, Can B, Bilge S, Ture H. Evaluation of antinociceptive and neurotoxic effects of intrathecal dexmedetomidine in rats. Balkan Med J. 2012;29:354
  • Bilge SS, Ilkaya F, Darakcı Ö, Çiftcioğlu E, Bozkurt A. Opioid receptors contribute to antinociceptive effect of tianeptine on colorectal distension-induced visceral pain in rats. Pharmacology. 2017;101:96-103.
  • Hoshino H, Obata H, Nakajima K, Mieda R, Saito S. The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg. 2015;120:460–6.
  • Hughes S, Hickey L, Donaldson LF, Lumb BM, Pickering AE. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone. Pain. 2015;156:328–34.
  • Pellissier G, Demenge P. Hypotensive and bradycardic effects elicited by spinal dopamine receptor stimulation. J Cardiovasc Pharmacol. 1991;18:548–55.
  • Jahanbani M, Nasri S, Pakdel FG, et al. The effect of acute intra locus coeruleus (lc) microinfusion of bupropion on formalin-induced pain behavior in rat. Basic Clin Neurosci. 2014;5:31–41.
  • Jesse CR, Wilhelm EA, Nogueira CW. Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion. Psychopharmacology (Berl). 2010;212:513–22.
  • Naderi S, Pakdel FG, Osalou MA, Cankurt U. Acute systemic infusion of bupropion decrease formalin induced pain behavior in rat. Korean J Pain. 2014;27:118–24.
  • Pedersen LH, Nielsen AN, 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;82:551–61.
  • Hache G, Coudore F, Gardier AM, Guiard BP. Monoaminergic antidepressants in the relief of pain: potential therapeutic utility of triple reuptake inhibitors (TRIs). Pharmaceuticals. 2011;4:285–342.
  • Piacentini MF, Clinckers R, Meeusen R, Sarre S, Ebinger G, Michotte Y. Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat. J Appl Physiol. 2003;95:652–6.
  • Nicholson R, Dixon AK, Spanswick D, Lee K. Noradrenergic receptor mRNA expression in adult rat superficial dorsal horn and dorsal root ganglion neurons. Neurosci Lett. 2005;380:316–21.
  • Vega JA, Amenta F, Hernandez LC, del Valle ME. Presence of catecholamine-related enzymes in a subpopulation of primary sensory neurons in dorsal root ganglia of the rat. Cell Mol Biol. 1991;37:519–30.
  • Hong Y, Abbott F v. Contribution of peripheral α1A-adrenoceptors to pain induced by formalin or by α-methyl-5-hydroxytryptamine plus noradrenaline. Eur J Pharmacol. 1996;301:41–8.
  • Gil DW, Wang J, Gu C, Donello JE, Cabrera S, Al-Chaer ED. Role of sympathetic nervous system in rat model of chronic visceral pain. J Neurogastroenterol Motil. 2016;28:423–31.
  • Fang F, Proudfit HK. Antinociception produced by microinjection of morphine in the rat periaqueductal gray is enhanced in the foot, but not the tail, by intrathecal injection of α1-adrenoceptor antagonists. Brain Res. 1998;790:14–24.
  • Kim SK, Park JH, Bae SJ, et al. Effects of electroacupuncture on cold allodynia in a rat model of neuropathic pain: mediation by spinal adrenergic and serotonergic receptors. Exp Neurol. 2005;195:430–6.
  • Danzebrink RM, Gebhart GF. Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of visceral nociception. J Pharmacol Exp Ther. 1990;253:698–705.
  • Gao X, Zhang Y qiu, Wu G cheng. Effects of dopaminergic agents on carrageenan hyperalgesia after intrathecal administration to rats. Eur J Pharmacol. 2001;418:73–7.
  • Shimizu T, Iwata S ichi, Morioka H, Masuyama T, Fukuda T, Nomoto M. Antinociceptive mechanism of l-DOPA. Pain. 2004;110:246–9.
  • Chen M, Hoshino H, Saito S, Yang Y, Obata H. Spinal dopaminergic involvement in the antihyperalgesic effect of antidepressants in a rat model of neuropathic pain. Neurosci Lett. 2017;649:116–23. 27.
  • Okumura T, Nozu T, Ishioh M, Igarashi S, Kumei S, Ohhira M. 5-HT2A receptors but not cannabinoid receptors in the central nervous system mediate levodopa-induced visceral antinociception in conscious rats. Naunyn Schmiedebergs Arch Pharmacol. 2020;393:1419–25.
  • Gültekin H, Ahmedov V. The roles of the opioidergic system and nitric oxide in the analgesic effect of venlafaxine. Yakugaku Zasshi. 2006;126:117–21.
  • Sikka P, Kaushik S, Kumar G, Kapoor S, Bindra V, Saxena K. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice. J Pharm Bioallied Sci. 2011;3:412.
  • Turan Yücel N, Kandemir Ü, Demir Özkay Ü, Can ÖD. 5-HT1A serotonergic, α-adrenergic and opioidergic receptors mediate the analgesic efficacy of vortioxetine in mice. Molecules. 2021;26:3242.
  • Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL. α(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. JPET. 2002;300:282–90.
  • Ulger F, Bozkurt A, Bilge SS, et al. The antinociceptive effects of intravenous dexmedetomidine in colorectal distension-induced visceral pain in rats: the role of opioid receptors. Anesth Analg. 2009;109:616–22.
  • Clark A, Tate B, Urban B, Schroeder R, Gennuso S, Ahmadzadeh S et al. Bupropion mediated effects on depression, attention deficit hyperactivity disorder, and smoking cessation. Health Psychol Res. 2023;11:81043.

Bupropionun visseral ağrı üzerindeki antinosiseptif etkisi ve etki mekanizması

Year 2024, Volume: 49 Issue: 2, 415 - 423, 30.06.2024
https://doi.org/10.17826/cumj.1429753

Abstract

Amaç: Bupropion, noradrenalin ve dopamin geri alımını inhibe eden bir antidepresandır. Bilimsel literatürde, bupropionun ağrı üzerindeki etkilerine ilişkin sınırlı bilgi bulunmaktadır ve bu bilgiler ağırlıklı olarak somatik ağrı çalışmalarından elde edilmiştir. Bu çalışmanın amacı, ilk kez olarak pür viseral ağrı modeli olan kolorektal distansiyon ile indüklenen viseral ağrıda bupropionun etkisini araştırmak ve bu etkide ağrı kontrolünde rol alan çeşitli reseptörlerin rolünü ortaya koymaktır.
Gereç ve Yöntem: Çalışmada erkek Sprague-Dawley sıçanlar kullanıldı. Viseral ağrı, kolorektal distansiyon ile indüklenen viseromotor yanıt ile değerlendirildi. Bupropion 5, 10, 20, 40 mg/kg dozlarında gastrik olarak uygulandı. Bupropionun omurilik seviyesindeki etki mekanizması, α1 ve α2 adrenoseptörlerinin, D1 ve D2 dopamin ve opioid reseptörlerinin antagonistlerinin bupropionun etkili dozundan 10 dakika önce intratekal olarak uygulanmasıyla araştırıldı.
Bulgular: Bupropion 20 ve 40 mg/kg intragastrik dozlarda anlamlı antinosiseptif etki göstermiş, bu iki doz arasında fark bulunmamıştır. İntratekal olarak uygulanan yohimbin (30 µg/sıçan), sülpirid (30 µg/ sıçan, i.t.) ve nalokson (2,5 µg/sıçan) bupropionun antinosiseptif etkisini azaltmıştır. Prazosin ve SCH 23390 bupropionun etkisini değiştirmemiştir.
Sonuç: Bulgular bupropionun visseral ağrıda antinosiseptif etkisini ve bu etkide omurilikteki adrenerjik, dopaminerjik ve opioiderjik reseptörlerin rol oynadığını göstermektedir.

Ethical Statement

Bu çalışma Ondokuz Mayıs Üniversitesi Hayvan Deneyleri Etik Kurulu tarafından 14/07/2020 tarihinde 2020/25 kabul numarası ile onaylanmıştır.

Supporting Institution

Ondokuz Mayıs Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi

Project Number

PYO.TIP.1904.20.012

References

  • Mico J, Ardid D, Berrocoso E, Eschlier A. Antidepressants and pain. Trends Pharmacol Sci. 2006;27:348–54.
  • Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017;18:2483.
  • Hajhashemi V, Minaiyan M, Banafshe HR, Mesdaghinia A, Abed A. The anti-inflammatory effects of venlafaxine in the rat model of carrageenan-induced paw edema. Iran J Basic Med Sci. 2015;18:654–8.
  • Schwartz ES, Gebhart GF. Visceral pain. In Behavioral Neurobiology of Chronic Pain (Eds BK Taylor, DP Finn): 171-97. Berlin, Springer. 2014.
  • Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry. 2004;06:159–66.
  • Hajhashemi V, Khanjani P. Analgesic and anti-inflammatory activities of bupropion in animal models. Res Pharm Sci. 2014;9:251–7.
  • Marinho BG, Miranda LS, da S Costa J, Leitão SG, Vasconcellos ML, Pereira VL et al. The antinociceptive properties of the novel compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one in acute pain in mice. Behav Pharmacol. 2013;24:10-9.
  • Isguzar O, Baris S, Bozkurt A, Can B, Bilge S, Ture H. Evaluation of antinociceptive and neurotoxic effects of intrathecal dexmedetomidine in rats. Balkan Med J. 2012;29:354
  • Bilge SS, Ilkaya F, Darakcı Ö, Çiftcioğlu E, Bozkurt A. Opioid receptors contribute to antinociceptive effect of tianeptine on colorectal distension-induced visceral pain in rats. Pharmacology. 2017;101:96-103.
  • Hoshino H, Obata H, Nakajima K, Mieda R, Saito S. The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg. 2015;120:460–6.
  • Hughes S, Hickey L, Donaldson LF, Lumb BM, Pickering AE. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone. Pain. 2015;156:328–34.
  • Pellissier G, Demenge P. Hypotensive and bradycardic effects elicited by spinal dopamine receptor stimulation. J Cardiovasc Pharmacol. 1991;18:548–55.
  • Jahanbani M, Nasri S, Pakdel FG, et al. The effect of acute intra locus coeruleus (lc) microinfusion of bupropion on formalin-induced pain behavior in rat. Basic Clin Neurosci. 2014;5:31–41.
  • Jesse CR, Wilhelm EA, Nogueira CW. Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion. Psychopharmacology (Berl). 2010;212:513–22.
  • Naderi S, Pakdel FG, Osalou MA, Cankurt U. Acute systemic infusion of bupropion decrease formalin induced pain behavior in rat. Korean J Pain. 2014;27:118–24.
  • Pedersen LH, Nielsen AN, 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;82:551–61.
  • Hache G, Coudore F, Gardier AM, Guiard BP. Monoaminergic antidepressants in the relief of pain: potential therapeutic utility of triple reuptake inhibitors (TRIs). Pharmaceuticals. 2011;4:285–342.
  • Piacentini MF, Clinckers R, Meeusen R, Sarre S, Ebinger G, Michotte Y. Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat. J Appl Physiol. 2003;95:652–6.
  • Nicholson R, Dixon AK, Spanswick D, Lee K. Noradrenergic receptor mRNA expression in adult rat superficial dorsal horn and dorsal root ganglion neurons. Neurosci Lett. 2005;380:316–21.
  • Vega JA, Amenta F, Hernandez LC, del Valle ME. Presence of catecholamine-related enzymes in a subpopulation of primary sensory neurons in dorsal root ganglia of the rat. Cell Mol Biol. 1991;37:519–30.
  • Hong Y, Abbott F v. Contribution of peripheral α1A-adrenoceptors to pain induced by formalin or by α-methyl-5-hydroxytryptamine plus noradrenaline. Eur J Pharmacol. 1996;301:41–8.
  • Gil DW, Wang J, Gu C, Donello JE, Cabrera S, Al-Chaer ED. Role of sympathetic nervous system in rat model of chronic visceral pain. J Neurogastroenterol Motil. 2016;28:423–31.
  • Fang F, Proudfit HK. Antinociception produced by microinjection of morphine in the rat periaqueductal gray is enhanced in the foot, but not the tail, by intrathecal injection of α1-adrenoceptor antagonists. Brain Res. 1998;790:14–24.
  • Kim SK, Park JH, Bae SJ, et al. Effects of electroacupuncture on cold allodynia in a rat model of neuropathic pain: mediation by spinal adrenergic and serotonergic receptors. Exp Neurol. 2005;195:430–6.
  • Danzebrink RM, Gebhart GF. Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of visceral nociception. J Pharmacol Exp Ther. 1990;253:698–705.
  • Gao X, Zhang Y qiu, Wu G cheng. Effects of dopaminergic agents on carrageenan hyperalgesia after intrathecal administration to rats. Eur J Pharmacol. 2001;418:73–7.
  • Shimizu T, Iwata S ichi, Morioka H, Masuyama T, Fukuda T, Nomoto M. Antinociceptive mechanism of l-DOPA. Pain. 2004;110:246–9.
  • Chen M, Hoshino H, Saito S, Yang Y, Obata H. Spinal dopaminergic involvement in the antihyperalgesic effect of antidepressants in a rat model of neuropathic pain. Neurosci Lett. 2017;649:116–23. 27.
  • Okumura T, Nozu T, Ishioh M, Igarashi S, Kumei S, Ohhira M. 5-HT2A receptors but not cannabinoid receptors in the central nervous system mediate levodopa-induced visceral antinociception in conscious rats. Naunyn Schmiedebergs Arch Pharmacol. 2020;393:1419–25.
  • Gültekin H, Ahmedov V. The roles of the opioidergic system and nitric oxide in the analgesic effect of venlafaxine. Yakugaku Zasshi. 2006;126:117–21.
  • Sikka P, Kaushik S, Kumar G, Kapoor S, Bindra V, Saxena K. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice. J Pharm Bioallied Sci. 2011;3:412.
  • Turan Yücel N, Kandemir Ü, Demir Özkay Ü, Can ÖD. 5-HT1A serotonergic, α-adrenergic and opioidergic receptors mediate the analgesic efficacy of vortioxetine in mice. Molecules. 2021;26:3242.
  • Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL. α(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. JPET. 2002;300:282–90.
  • Ulger F, Bozkurt A, Bilge SS, et al. The antinociceptive effects of intravenous dexmedetomidine in colorectal distension-induced visceral pain in rats: the role of opioid receptors. Anesth Analg. 2009;109:616–22.
  • Clark A, Tate B, Urban B, Schroeder R, Gennuso S, Ahmadzadeh S et al. Bupropion mediated effects on depression, attention deficit hyperactivity disorder, and smoking cessation. Health Psychol Res. 2023;11:81043.
There are 35 citations in total.

Details

Primary Language English
Subjects Sensory Systems
Journal Section Research
Authors

İsa Yeşilyurt 0000-0002-2164-4580

Özge Darakcı Saltık 0000-0002-2871-2435

Ayhan Bozkurt 0000-0002-5794-709X

Project Number PYO.TIP.1904.20.012
Publication Date June 30, 2024
Submission Date February 2, 2024
Acceptance Date May 18, 2024
Published in Issue Year 2024 Volume: 49 Issue: 2

Cite

MLA Yeşilyurt, İsa et al. “Antinociceptive Effect of Bupropion on Visceral Pain and Its Mechanism of Action”. Cukurova Medical Journal, vol. 49, no. 2, 2024, pp. 415-23, doi:10.17826/cumj.1429753.