Gabapentin enhances anti-nociceptive effects of morphine on heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain

Document Type: Original Article


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

2 Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran

3 Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan. Iran 5 Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

4 Physiology Research Center, Kashan University of Medical Sciences, Kashan. Iran .Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan. Iran

5 Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan. Iran Physiology Research Center, Kashan University of Medical Sciences, Kashan. Iran


Objective(s):Neuropathic pain is caused by lesions or diseases affecting the somatosensory system and often responds poorly to typical medications.  In this study, we evaluated anti-nociceptive effects of morphine, gabapentin and their combination on heat hyperalgesia, cold and mechanical allodynia in chronic constriction injury (CCI) model of neuropathic pain in rats.
Materials and Methods: Morphine (2, 4 and 8 mg/kg) and gabapentin (5, 10 and 20 mg/kg) were administered either alone or in combination (morphine 2 mg/kg and gabapentin 5 mg/kg).
Results:Our results showed that morphine and gabapentin alone produce anti-nociceptive effects at higher doses (morphine 4 and 8 mg/kg and gabapentin 10 and 20 mg/kg) whereas their combination resulted in better analgesia at lower doses as compared to other treatment groups (morphine 2 mg/kg or gabapentin 5 mg/kg).
Conclusion: These findings suggest that gabapentin potentiates the analgesic effects of morphine in the chronic constriction injury (CCI) model of neuropathic pain and combination of these drugs may be considered as a beneficial treatment for neuropathic pain.


1. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al.  Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70:1630-1635.

2. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010; 150:573-581.

3. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33:87-107.

4. Rose MA, Kam PC.  Gabapentine : pharmacology and its use  in pain management. Anethesia 2002; 57:451-462.

5. Turan A, Karamanlioglu B, Memis D, Hamamcioglu MK, Tukenmez B, Pamukcu Z, et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004; 100:935-938.

6. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, et al. Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 2013; 65:223-254.

7. Dworkin RH, Oconor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS. Pharmacologic management of neuropathic pain: evidence-based recommendation. Pain 2007; 132:237-51.

8. Gilron I, Max MB, Combination pharmacotherapy for neuropathic pain: current evidence and further directions. Expert Rev Nerother 2005; 5:823-830.

9. Meymandi MS, Sepehri GR, Mobasher M. Gabapentin enhances analgesic response to morphine in acute model of pain in male rats. Pharmacol Biochem Behav 2006; 85:185-189.

10. Matthews EA, Dickenson AH. A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy. Anesthesiology 2002; 96:633-640.

11. Arciniega MD, Diaz-Reval MI, Cortes-Arroyo, Ramirez AM, Munoz FJ. Anti-nociceptive synergism of morphine and gabapentin in neuropathic pain induced by chronic constriction injury. Pharmacol Biochem Behav 2009; 92:457-464.

12. Banafshe HR, Mesdaghinia A, Arani MN, Ramezani MH, Heydari A, Hamidi GA.  Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system. Pharmacol Biochem Behav 2012; 100:425-430.

13. Tal M, Bennett GJ. Extra –territorial pain in rat with a peripheral mononeuropathy: mechano –hyperalgesia and mechano – allodynia in the territory of an uninjerd nerve. Pain1994; 57:375 – 382.

14. Pahlavan Y, Sepehri G, Sheibani V, Afarinesh Khaki M, Gojazadeh M, Pahlavan B, et al. Study the antinociceptive effect of intracerebroventricular injection of aqueous extract of origanum vulgare leaves in rat: possible involvement of opioid system. Iran J Basic Med Sci 2013; 16:1109-1113.

15. 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.

16. Karimi G, Hosseinzadeh H, Rassoulzadeh M, Razavi B, Taghiabadi E. Antinociceptive Effect of Elaeagnus angustifolia Fruits on Sciatic, Nerve Ligated Mice. Iran J Basic Med Sci 2010; 13:97-101.

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. Babaei-Balderlou F, Zare S, Heidari R, Farrokhi F. Effects of melatonin and vitamin E on peripheral neuropathic pain in streptozotocin-induced diabetic rats. Iran J Basic Med Sci 2010; 13:1-8.

19. Seltzer Z, Dubner R, Shir Y. A novel behavioural model of neuropathic pain  disorders produced in rats by partial sciatic nerve injury. Pain 1990; 43:205-218.

20. Palecek J, Dougherty PM, Kim SH, Paleckova V, Lekan H, Chung JM, et al. Responses of spinothalamic tract neurons to mechanical and thermal stimuli in an experimental model of peripheral neuropathy in primates. J Neurophysiol 1992;  68:1951-1966.
21. Ro LS, Jacobs JM. The role of the saphenous nerve in experimental sciatic nerve mononeuropathy produced by loose ligatures: a behavioral study. Pain 1993; 52:359-369.

22. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 1994; 59:369-376.

23. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2002; 18:350-354.

24. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003; 60:1524-1534.

25. Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo- controlled trial. Neurology 2002; 59:1015-1021.

26. Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003; 105:71-78.

27. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280:1837-1842.

28. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280:1831-1836.

29. Luo ZD, Calcutt NA, Higuera ES, Valder CR, Song YH, Svensson CI, et al. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther 2002; 303:1199-1205.

30. Field MJ, Oles RJ, Lewis AS, McCleary S, Hughes J, Singh L. Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents. Br J Pharmacol 1997; 121:1513-1522.

31. Shimoyama M, Shimoyama N, Inturrisi CE, Elliott KJ. Gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test. Pain 1997; 72:375-382.

32. Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000; 91:185-191.

33. Gilron I, Biederman J, Jhamandas K, Hong M. Gabapentin blocks and reverses antinociceptive morphine tolerance in the rat paw-pressure and tail-flick tests. Anesthesiology 2003; 98:1288-1292.

34. Babaei R, Javadi-Paydar M, Sharifian M, Mahdavian S, Almasi-Nasrabadi M, Norouzi A, et al. Involvement of nitric oxide in pioglitazone memory improvement in morphine-induced memory impaired mice. Pharmacol Biochem Behav 2012; 103:313-321.

35. Ezzatabadipour M, Majidi M, Malekpour-Afshar R, Eftekharvaghefi SH, Nematollahi-Mahani SN. The effects of morphine on tissue structure of the growth plate in male rats. Iran J Basic Med Sci 2011; 14:514-520.

36. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic

review of their efficacy and tolerability. Epilepsia 1997; 38:859-880.

37. Singh L, Field MJ, Ferris P, Hunter JC, Oles RJ, Williams RG, et al. The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine. Psychopharmacology (Berl) 1996; 127:1-9.

38. Carlton SM, Zhou S. Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. Pain 1998; 76:201-207.

39. Banafshe HR, Hamidi GA, Noureddini M, Mirhashemi SM, Mokhtari R, Shoferpour M. Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system. Eur J Pharmacol. 2014; 723:202-206.