Antinociceptive effects of maprotiline in a rat model of peripheral neuropathic pain: possible involvement of opioid system

Document Type : Original Article


1 Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran

2 Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran

3 Department of Pharmacology and Toxicology and Isfahan Pharmaceutical Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran


Objective(s): Neuropathic pain remains a clinical problem and is poorly relieved by conventional analgesics. This study was designed to determine whether maprotiline administration was effective in alleviating symptoms of neuropathic pain and whether the antinociceptive effect of maprotiline mediated through the opioid system.
Materials and Methods: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats, which resulted in thermal hyperalgesia, and mechanical and cold allodynia. Maprotiline (10, 20 and 40 mg/kg, IP) was administered on the 7th and 14th days after surgery. To study the role of the opioid system in the antinociceptive effects of maprotiline, maprotiline (20 mg/kg, IP) was administered in combination with naloxone (1 mg/kg, SC) on the 7th post-surgery day. Behavioral tests were done at 45 min after drug injections on the 7th and 14th days after surgery.
Results:Systemic administration of maprotiline blocked heat hyperalgesia, cold allodynia and reduced mechanical allodynia. Also antihyperalgesic effect of maprotiline was reversed by pretreatment with naloxone.
Conclusion: Our results suggest that maprotiline can be considered a potential therapeutic for the treatment of neuropathic pain, and the opioid system may be involved in the antihyperalgesic effects of maprotiline.


1. Zhuo M. Neuronal mechanism for neuropathic pain. Mol Pain 2007; 3:1–9.
2. Ro L S, Jacobs J M. The role of the saphenous nerve in experimental sciatic nerve mononeuropathy produced by loose ligatures: a behavioral study. Pain 1993; 52:359-369.
3. Guindon J, Hohmann AG. Recent advances in the pharmacological management of pain. Drugs 2007; 67:2121–2133.
4. Bennett G, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33:87-107.
5. Zychowska M, Rojewska E, Makuch W, Przewlocka B, Mika J. The influence of microglia activation on the efficacy of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine in a rat model of neuropathic pain. Eur J Pharmacol. 2015; 749:115-123.
6. Hajhashemi V, Banafshe HR, Minaiyan M, Mesdaghinia A,  Abed A. Antinociceptive effects of venlafaxine in a rat model of peripheral neuropathy: Role of alpha2-adrenergic receptors. Eur J Pharmacol. 2014; 5:230-236.
7. Ahles S, Gwirtsman H, Halaris A, Shah P, Schwarcz G, Hill MA. Comparative cardiac effects of maprotiline and doxepin in elderly depressed patients. J Clin Psychiatry 1984; 45:460–465.
8. Gruter W, Poldinger W, Maprotiline.  Mod Probl Pharmacopsychiatry. 1982; 18:17–48.
9. Nakajima K, Obata H, Iriuchijima N, Saito S. An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat. Pain 2012; 153:990-997.
10. Yokogawa F, Kiuchi Y, Ishikawa Y, Otsuka N, Masuda Y, Oguchi K, et  al. An investigation of monoamine-receptorsinvolved in antinociceptiveeffects of antidepressants. Anesth Analg 2002; 95:163-168.
11. Korzeniewska-Rybicka I, Plaznik A. Supraspinally mediated analgesic effect of antidepressant drugs. Pol J Pharmacol 2000; 52:93–99.
12. Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindstrom T, Thorell LH. A comparison of amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain 1997; 13:313-323.
13. Watson CP, Chipman M, Reed K, Evans RJ, Birkett N. Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain 1992; 48: 29-36.
14. Obata H, Saito S, Koizuka S, Nishikawa K, Goto F. The monoamine-mediated antiallodyniceffects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg 2005; 100:1406-1410.
15. Pettersen VL, Zapata-Sudo G, Raimundo JM, Trachez MM, Sudo RT. The synergistic interaction between morphine and maprotiline after intrathecal injection in rats. Anesth Analg 2009; 109:1312-1317.
16. Lee RL, Spencer PS. Effect of tricyclic antidepressants on analgesic activity in laboratory animals. Postgrad Med J 1980; 1:19-24.
17. Verdi J, Jafari-Sabet M, Mokhtari R, Mesdaghinia A, Banafshe HR. The effect of progesterone on expression and development of neuropathic pain in a rat model of peripheral neuropathy. Eur J Pharmacol 2013; 699:207-212.
18. Amin B, Hajhashemi V, Hosseinzadeh H, Abnous Kh. Antinociceptive evaluation of ceftriaxone and minocycline alone and in combination in a neuropathic pain model in rat. Neuroscience 2012; 224:15-25.
19. Banafshe HR, Mesdaghinia A, Arani MN, Ramezani MH, Heydari A, HamidiGA.  Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system. Pharmacol Biochem Behav 2012; 100:425-430.
20. Banafshe H, Hamidi GA, Noureddini M, Mirhashemi M, Mokhtaria M, Shoferpour M. Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system. Eur J Pharmacol 2014; 723:202-206.
21. Hamidi GA, Ramezani MH, Arani MN, Talaei SA, Mesdaghinia A, Banafshe HR. Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain. Eur J Pharmacol 2012; 674:260-264.
22. Hajhashemi V, Sadeghi H, Minaiyan M, Movahedian A, Talebi A. Central and peripheral anti-inflammatory effects of maprotiline on carrageenan-induced paw edema in rats. Inflamm Res 2012; 59:1053-1059.
23. Darcym P, Dredge K, Kellehir P, Kelly JP, Leonard BE, Chambers PL. Acutetoxicityprofile of maprotiline in the rat. Pharmacol Toxicol 1999; 85:276-281.
24. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000; 20:449–458.
25. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Evidence-based data from animal and human experimental studies on pain relief with antidepressants: a structured review. Pain Med 2000; 1:310–316.
26. McQuay JH, Tramer M, Nue BA, Carroll D, Wiffen PJ, Moore RA. A systematic review of antidepressants in neuropathic pain. Pain 1996; 68:217–227.
27. Jia HB, Wang XM, Qiu LL, Liu XY, Shen JC, Ji Q, et al. Spinal neuroimmune activation inhibited by repeated administration of pioglitazone in rats after L5 spinal nerve transection. Neurosci Lett 2013; 543:130-135.
28. Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynapthic Ca²⁺ channel complex. Nat Med 2011; 17:822-829.
29. Goff JR, Burkey AR, Goff DJ, Jasmin L. Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour. Neuroscience 1998; 82:559–574.
30. Porreca F, Tang QB, Bian D, Riedl M, Elde R, Lai J. Spinal opioid mu receptor expressionin lumbar spinal cord of rats following nerve injury. Brain Res 1998; 795:197-203.
31. Rashid MH, Inoue M, Toda K, Ueda H. Loss of peripheral morphine analgesia contributesto the reduced effectiveness of systemic morphine in neuropathic pain. J Pharmacol Exp Ther 2004; 309: 380–387.
32. Back SK, Lee J, Hong SK, Na HS. Loss of spinal mu-opioid receptor is associated with mechanical allodynia in a rat model of peripheral neuropathy. Pain 2006; 123:117-126.
33. Yeomans DC, Proudfit HK. Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: behavioral evidence. Pain 1996; 68:133–140.
34. Gautron M, Jazat F, Ratinahirana H, Hauw JJ, Guilbaud G. Alterations in myelinated fibres in the sciatic nerve of rats after constriction: possible relationships between the presence of abnormal small myelinated fibres and pain-related behavior. Neurosci Lett 1990; 111:28–33.
35. Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. TRPM8 is required for cold sensation in mice. Neuron 2007; 54:371–378.