Chronic migraine caused a higher rate of tendency to cannabinoid agonist compared to morphine Tendency to use cannabis in chronic Migraine

Main Article Content

Mojdeh Mansoori
Mohammad Reza Zarei
Goli Chamani
Masoud Nazeri
Fatemeh Mohammadi
Samane Sadat Alavi
Mohammad Shabani


Keywords:  Migraine, Nitroglycerin, Morphine, WIN 55,212-2, Conditioned place preference


Background and aim: Opioid and cannabinoid systems have considerable roles in modulation of chronic pain as well as regulation reward circuit and addiction responses. This study investigated the effect of nitroglycerin (NTG)-induced migraine attack on the acquisition of morphine and cannabinoid-induced conditioned place preference (CPP) in male rats.

Methods: Adult male rats (230-250 gr) were used. Experimental groups were included (n=10): control, opioid receptor agonist morphine (10mg/kg), WIN55,212-2 (1mg/kg) as a cannabinoid receptor agonist, NTG + morphine (10mg/kg) and NTG + WIN55,212-2 (1mg/kg). Nitroglycerin (10 mg/kg) was used to induce migraine attack every other day for 9 days. After migraine induction, conditioning performance was assessed by CPP test. During conditioning days, morphine and WIN55,212-2 were injected subcutaneously and intraperitoneally, respectively. Anxiety and locomotor activity were evaluated using open field test (OFT).

Results: According to data, conditioning score for morphine-treated rats was significantly decreased following NTG-induced migraine. However, NTG-induced migraine was able to increase the conditioning score in WIN55,212-2 as compared to control group.  In OFT, there were no significant differences in locomotor activity and grooming behaviors between experimental groups. However, time spent in the center of OFT box was significantly decreased in NTG plus morphine-treated rats as compared to control. Moreover, rearing response in NTG-treated groups which received either morphine or WIN55,212-2 decreased as compared to control group.

Conclusion: NTG induced migraine prompts a decrease in morphine and an increase in cannabinoid performances. So, these compounds effects on drug dependency during migraine attack may occur at different mechanism or mechanisms.



Download data is not yet available.


Metrics Loading ...
Abstract 79 | PDF Downloads 29


1. Gölöncsér F, Sperlágh B. Effect of genetic deletion and pharmacological antagonism of P2X7 receptors in a mouse animal model of migraine. J Headache Pain. 2014; 15(1):24.
2. Sufka KJ, Staszko SM, Johnson AP, Davis ME, Davis RE, Smitherman TA. Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats. J Headache Pain. 2016; 17(1):1-7.
3. Messali A, Sanderson JC, Blumenfeld AM, et al. Direct and Indirect Costs of Chronic and Episodic Migraine in the United States: A Web‐Based Survey. Headache: J Headache Pain. 2016; 56(2):306-22.
4. Trescot AM, Helm S, Hansen H, et al. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians’(ASIPP) Guidelines. Pain physician. 2008;11(2 Suppl): S5-S62.
5. Beal BR, Wallace MS. An Overview of Pharmacologic Management of Chronic Pain. Med Clin North Am. 2016; 100(1):65-79.
6. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008; 71(22):1821-8.
7. Holland P, Akerman S, Goadsby P. Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat. Eur J Neurosci. 2006; 24(10):2825-33.
8. Hill KP, Palastro MD, Johnson B, Ditre JW. Cannabis and pain: a clinical review. Cannabis Cannabinoid Res. 2017; 2(1):96-104.
9. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What Percentage of Chronic Nonmalignant Pain Patients Exposed to Chronic Opioid Analgesic Therapy Develop Abuse/Addiction and/or Aberrant Drug‐Related Behaviors? A Structured Evidence‐Based Review. Pain Med. 2008; 9(4):444-59.
10. Pagé MG, Saïdi H, Ware MA, Choinière M. Risk of Opioid Abuse and Biopsychosocial Characteristics Associated With This Risk Among Chronic Pain Patients Attending a Multidisciplinary Pain Treatment Facility. Clin J Pain. 2016; 32(10):859-69.
11. Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci. 2001; 2(10):695-703.
12. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain. 2018 Feb 21; 19(1):17.
13. Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache. 2018; 58(7):1139-86.
14. Greco R, Tassorelli C. Endocannabinoids and migraine. Cannabinoids in Neurologic and Mental Disease. 2015:173.
15. Bardo M, Bevins RA. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology. 2000; 153(1):31-43.
16. Sáenz JCB, Villagra OR, Trías JF. Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social and isolated reared rats. Behavi Brain Res. 2006; 169(1):57-65.
17. Ferrari LF, Levine JD, Green PG. Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat. Neuroscience. 2016; 317:121-9.
18. Benemei S, Nicoletti P, Capone J, Geppetti P. Pain pharmacology in migraine: focus on CGRP and CGRP receptors. Neurological Sciences. 2007;: S89-S93.
19. Greco R, Bandiera T, Mangione A, et al. Effects of peripheral FAAH blockade on NTG-induced hyperalgesia—evaluation of URB937 in an animal model of migraine. Cephalalgia. 2015; 35(12):1065-76.
20. Becerra L, Breiter HC, Wise R, Gonzalez RG, Borsook D. Reward circuitry activation by noxious thermal stimuli. Neuron. 2001; 32(5):927-46.
21. Bushnell MC, Čeko M, Low LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci. 2013; 14(7):502-11.
22. Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A. Characterization of a novel model of chronic migraine. PAIN®. 2014;155(2):269-74.
23. Marchalant Y, Rosi S, Wenk GL. Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. Neuroscience. 2007; 144(4):1516-22.
24. Pascual D, Goicoechea C, Suardíaz M, Martín MI. A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats. Pain. 2005; 118(1):23-34.
25. Malone DT, Taylor DA. Modulation by fluoxetine of striatal dopamine release following Δ9‐tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol. 1999; 128(1):21-6.
26. Melis M, Gessa GL, Diana M. Different mechanisms for dopaminergic excitation induced by opiates and cannabinoids in the rat midbrain. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2000; 24(6):993-1006.
27. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci India Sect B Biol Sci. 2002; 99(12):8384-8.
28. Pistis M, Muntoni AL, Pillolla G, Gessa GL. Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study. Eur J Neurosci. 2002; 15(11):1795-802.
29. Kim PS, Fishman MA. Cannabis for Pain and Headaches: Primer. Current pain and headache reports. 2017; 21(4):19.
30. Maldonado R. Study of cannabinoid dependence in animals. Pharmacology & therapeutics. 2002; 95(2):153-64.
31. Robbe D, Alonso G, Duchamp F, Bockaert J, Manzoni OJ. Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci. 2001; 21(1):109-16.
32. Sarchielli P, Alberti A, Russo S, et al. Nitric oxide pathway, Ca2+, and serotonin content in platelets from patients suffering from chronic daily headache. Cephalalgia. 1999; 19(9):810-6.
33. Mackie K. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. nt J Obes. 2006; 30: S19-S23.
34. Chaparro LE, Furlan AD, Deshpande A, Mailis‐Gagnon A, Atlas S, Turk DC. Opioids compared to placebo or other treatments for chronic low‐back pain. The Cochrane Library. 2013.
35. Laxmaiah Manchikanti M, Vallejo R, IV M. Effectiveness of long-term opioid therapy for chronic non-cancer pain. Pain physician. 2011; 14: E133-E56.
36. Portenoy RK. Opioid therapy for chronic nonmalignant pain. Pain research and management. 1996; 1(1):17-28.
37. Aronoff GM. Opioids in chronic pain management: is there a significant risk of addiction? Current Pain and Headache Reports. 2000; 4(2):112-21.
38. Yamamoto T, Nair P, Vagner J, et al. A structure–activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are δ/μ opioid receptor agonists and neurokinin 1 receptor antagonists. Journal of medicinal chemistry. 2008; 51(5):1369.
39. Ozaki S, Narita M, Narita M, et al. Suppression of the morphine‐induced rewarding effect in the rat with neuropathic pain: implication of the reduction in µ‐opioid receptor functions in the ventral tegmental area. J Nerochem. 2002; 82(5):1192-8.
40. Matthes HW, Maldonado R, Simonin F, Valverde O. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature. 1996; 383(6603):819.
41. Corder G, Tawfik VL, Wang D, et al. Loss of [mu] opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nature Med. 2017.
42. Koob GF. A role for brain stress systems in addiction. Neuron. 2008; 59(1):11-34.
43. van Wijk A, Lindeboom JA, de Jongh A, Tuk JG, Hoogstraten J. Pain related to mandibular block injections and its relationship with anxiety and previous experiences with dental anesthetics. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012; 114(5): S114-S9.
44. Raoof M, Ebrahimnejad H, Abbasnejad M, et al. The effects of inflammatory tooth pain on anxiety in adult male rats. Basic and clinical neuroscience. 2016; 7(3):259.
45. Bahaaddini M, Khatamsaz S, Esmaeili-Mahani S, Abbasnejad M, Raoof M. The role of trigeminal nucleus caudalis orexin 1 receptor in orofacial pain-induced anxiety in rat. NeuroReport. 2016;27(15):1107-13.
46. Minen MT, De Dhaem OB, Van Diest AK, et al. Migraine and its psychiatric comorbidities. J Neurolog, Neurosurg & Psychiatry. 2016;87(7):741-9.
47. Costa A, Smeraldi A, Tassorelli C, Greco R, Nappi G. Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats. Neurosci lett. 2005; 383(1):7-11.
48. Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods JH. Nonpeptidic δ-opioid receptor agonists reduce immobility in the forced swim assay in rats. Neuropsychopharmacology. 2002; 26(6):744-55
49. Joshi JC, Ray A, Gulati K. Effects of morphine on stress induced anxiety in rats: role of nitric oxide and Hsp70. Physio & Behav. 2015; 139:393-6.
50. Narita M, Kaneko C, Miyoshi K, et al. Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacology. 2006; 31(4):739-50.
51. Narita M, Kuzumaki N, Narita M, et al. Chronic pain‐induced emotional dysfunction is associated with astrogliosis due to cortical δ‐opioid receptor dysfunction. J Neurochem. 2006; 97(5):1369-78.
52. Morena M, Patel S, Bains JS, Hill MN. Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology. 2016; 41(1):80-102.
53. Buckner JD, Schmidt NB, Lang AR, Small JW, Schlauch RC, Lewinsohn PM. Specificity of social anxiety disorder as a risk factor for alcohol and cannabis dependence. J Psychiatr Res. 2008; 42(3):230-9.