Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats

Mohammad Reza Zohrehvand; Reza Kazemi; Mohammad Hassan Mirasheh; Farideh Bahrami; Mohammad Ali Zabihian; Gholam Hossein Meftahi; Mehdi Rahimi-nasrabadi; Zahra Bahari

Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats

Abstract

: It is believed that α-adrenoceptors have critical contribution in the process of pain information. Anterior cingulate of cortex (ACC) is a key area of brain associated with pain perception. Pharmacological studies demonstrated that crocin, as a potent antioxidant, has analgesic effects. The underlying analgesic mechanism of the crocin is far from clear. Therefore, the present study was design to examine the interaction of anti-nociceptive effects of crocin with α1- and α2-adrenoceptors of ACC in chronic constriction injury (CCI) model of neuropathic pain. Intra-ACC injection of crocin significantly decreased cold allodynia (using acetone test) and anxiety (using elevated plus maze test) in neuropathic rats from 2 days to 6 days’ post-surgery. Co-injection of crocin and prazosin (α1-adrenoceptors antagonist, 30 μg/5μl) had no effect on the allodynia. However, co-injection of crocin and yohimbine (α2-adrenoceptors antagonist, 30 μg/5μl) significantly increased the allodynia on days 4 and 6 post-surgery as compared with CCI+crocin rats. Moreover, our data identified that neuropathy decreased open arm entries and locomotor activity. Additionally, crocin increased entries to open arms; but this increase was not significant as compared to CCI group. There was no significant difference between CCI+Crocin and CCI+crocin+prazosin groups. However, co-injection of crocin and yohimbine significantly decreased entries to open arms as compared with CCI+crocin group. Furthermore, co-injection of crocin with prazosin or yohimbine did not cause significant changes in locomotor activity. The present study suggested that the anti-nociceptive and anxiolytic effects of crocin appear to be mediated through α2-, and not α1-adrenoceptors in the ACC.

Keywords

References

[1] Alles SR, Smith PA. Etiology and Pharmacology of Neuropathic Pain. Pharmacol Rev. 2018; 70(2): 315-347. [CrossRef]
[2] Bahari Z, Sadr SS, Meftahi GH, Ghasemi M, Manaheji H, Mohammadi A, Mehranfard N. Nerve injury-induced plasticity in the nociceptive pathways. Arch Neurosci. 2014; 2(2): 18214. [CrossRef]
[3] Ferreira-Chamorro P, Redondo A, Riego G, Leanez S, Pol O. Sulforaphane inhibited the nociceptive responses, anxiety- and depressive-like behaviors associated with neuropathic pain and improved the anti-allodynic effects of morphine in mice. Front Pharmacol. 2018; 9: 1332. [CrossRef]
[4] Chen H, Hu Y, Xie K, Chen Y, Wang H, Bian Y, Wang Y, Dong A, Yu Y. Effect of autophagy on allodynia, hyperalgesia and astrocyte activation in a rat model of neuropathic pain. Int J Mol Med. 2018; 42: 2009-2019. [CrossRef]
[5] Bahari Z, Meftahi GH. Spinal α2‐ adrenoceptors and neuropathic pain modulation; therapeutic target. Br J Pharmacol. 2019; 176(14): 2366-2381. [CrossRef]
[6] Nakai K, Nakae A, Kubo T, Minegishi Y, Fujino Y, Hosokawa K. Contribution to pain-related behavior by various types of spinal alpha 2 adrenergic receptor in a rat model of trigeminal neuropathic pain. Anesth Analg. 2016; 123(3): 417. [CrossRef]
[7] Sudo RT, do Amaral RV, da Silva Monteiro CEDS, Pitta IDR, Lima MDC, Montes GC, Ririe DG, Hayashida K, ZapataSudo G. Antinociception induced by a novel α2A adrenergic receptor agonist in rodents acute and chronic pain models. Eur J Pharmacol. 2017; 815: 210-218. [CrossRef]
[8] Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML. The anterior cingulate cortex and pain processing. Front Integr Neurosci. 2014; 8: 35. [CrossRef]

[9] Moon HC, Heo WI, Kim YJ, Lee D, Won SY, Kim HR, Ha SM, Lee YJ, Park YS. Optical inactivation of the anterior cingulate cortex modulate descending pain pathway in a rat model of trigeminal neuropathic pain created via chronic constriction injury of the infraorbital nerve. J Pain Res. 2017; 10: 2355–2364. [CrossRef]
[10] Sellmeijer J, Mathis V, Hugel S, Li XH, Song Q, Chen QY, Barthas F, Lutz PE, Karatas M, Luthi A, Veinante P, Aertsen A, Barrot M, Zhuo M, Yalcin I. Hyperactivity of anterior cingulate cortex areas 24a/24b drives chronic pain-induced anxiodepressive-like consequences. J Neurosci. 2018; 38(12): 3102-3115. [CrossRef]
[11] Safakhah HA, Taghavi T, Rashidy-Pour A, Vafaei AA, Sokhanvar M, Mohebbi N, Rezaei-Tavirani M. Effects of saffron (Crocus sativus L.) stigma extract and its active constituent crocin on neuropathic pain responses in a rat model of chronic constriction injury. Iran J Pharm Res. 2016; 15(1): 253–261.
[12] Chien MY, Ku YH, Chang JM, Yang CM, Chen CH. Effects of herbal mixture extracts on obesity in rats fed a high-fat diet. J Food Drug Anal. 2016; 24(3): 594-601. [CrossRef]
[13] Park JP, Kim JH, Park MK, Yu JW. Potential agents for cancer and obesity treatment with herbal medicines from the green garden. Biotechnol Bioprocess Eng. 2011; 16: 1065-1076. [CrossRef]
[14] Moradi B, Abbaszadeh S, Shahsavari S, Alizadeh M, Beyranvand F. The most useful medicinal herbs to treat diabetes. Biomed Res Ther. 2018; 5(8): 2538-2551. [CrossRef]
[15] Talebanzadeh S, Ashrafi M, Kazemipour N, Erjaee H, Nazifi S. Evaluation of the effects of saffron aqueous extract on oxidative stress in the lens of streptozotocin-induced diabetic rats. Biomed Res Ther. 2018; 5(4): 2133-2141. [CrossRef]
[16] Ramli FN, Sajak AA, Abas F, Mat Daud ZA, Azlan A. Effect of Saffron Extract and Crocin in Serum Metabolites of Induced Obesity Rats. Biomed Res Int. 2020; 2020: 1247946. [CrossRef]
[17] Srivastava R, Ahmed H, Dixit RK, Dharamveer, Saraf SA. Crocus sativus L.: A comprehensive review. Pharmacogn Rev. 2010; 4(8): 200–208. [CrossRef]
[18] Rahmani AH, Khan AA, Aldebasi YH. Saffron (Crocus sativus) and its Active Ingredients: Role in the Prevention and Treatment of Disease. Pharmacogn J. 2017; 9(6): 873-879. [CrossRef]
[19] Samarghandian S, Azimi-Nezhad M, Samini F, Farkhondeh T. The Role of Saffron in Attenuating Age-related Oxidative Damage in Rat Hippocampus. Recent Pat Food Nutr Agric. 2017; 8(3): 183-189. [CrossRef]
[20] Yaribeygi H, Mohammadi MT, Sahebkardef AH. Crocin potentiates antioxidant defense system and improves oxidative damage in liver tissue in diabetic rats. Biomedicine & Pharmacotherapy. 2018; 98: 333-337. [CrossRef]
[21] Asrari N, Yazdian-Robati R, Abnous K, Razavi BM, Rashednia M, Hasani FV, Hosseinzadeh H. Antidepressant effects of aqueous extract of saffron and its effects on CREB, P-CREB, BDNF, and VGF proteins in rat cerebellum. J Pharmacopunct. 2018; 21(1): 35-40. [CrossRef]
[22] Sadeghnia HR, Shaterzadeh H, Forouzanfar F, Hosseinzadeh H. Neuroprotective effect of safranal, an active ingredient of crocus sativus, in a rat model of transient cerebral ischemia. Folia Neuropathol. 2017; 55(3): 206-213. [CrossRef]
[23] Amin B, Hosseini S, Hosseinzadeh H. Enhancement of antinociceptive effect by co-administration of amitriptyline and crocus sativus in a rat model of neuropathic pain. Iran J Pharm Res. 2017; 16(1): 187–200.
[24] Zeinaliorcid M, Zirak MR, Rezaeeorcid SA, Karimi G, Hosseinzadeh H. Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review. IJBMS. 2019; 22(4): 334-344. [CrossRef]
[25] Pitsikas N. Constituents of saffron (Crocus sativus L.) as potential candidates for the treatment of anxiety disorders and schizophrenia. Molecules. 2016; 21(3): 303. [CrossRef]
[26] Safakhah HA, Taghavi T, Rashidy-Pour A, Vafaei AA, Sokhanvar M, Mohebbi N, Rezaei-Tavirani M. Effects of Saffron (Crocus sativus L.) Stigma Extract and its Active Constituent Crocin on Neuropathic Pain Responses in a Rat Model of Chronic Constriction Injury. Iran J Pharm Res. 2016; 15(1): 253-261.
[27] Wang JF, Xu HJ, He ZL, Yin Q, Cheng W. Crocin Alleviates Pain Hyperalgesia in AIA Rats by Inhibiting the Spinal Wnt5a/β-Catenin Signaling Pathway and Glial Activation. Neural Plast. 2020; 2020: 4297483. [CrossRef]
[28] Zhi MJ, Liu K, Zheng ZL, He X, Li T, Sun G, Zhang M, Wang FC, Gao XY, Zhu B. Application of the chronic constriction injury of the partial sciatic nerve model to assess acupuncture analgesia. J Pain Res. 2017; 10: 2271-2280. [CrossRef]
[29] Sadeghi M, Manaheji H, Haghparast A, Zaringhalam J, Nazemi S, Bahari Z. Study of the effect of GABAA receptor and glial inhibition on behavioral responses in CCI model of neuropathic pain in rat. ISMJ. 2015; 17(6): 1120-1134.
[30] Murasawa H, Kobayashi H, Saeki K, Kitano Y. Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain. Psychopharmacology. 2020; 237(1): 189- 197. [CrossRef]
[31] Tamaddonfard E, Farshid AA, Ahmadian E, Hamidhoseyni A. Crocin enhanced functional recovery after sciatic nerve crush injury in rats. Iran J Basic Med Sci. 2013; 16(1): 83-90.
[32] Tamaddonfard E, Farshid AA, Maroufi S, Kazemi-Shojaei S, Erfanparast A, Asri-Rezaei S, Taati M, Dabbaghi M, Escort M. Effects of safranal, a constituent of saffron, and vitamin E on nerve functions and histopathology following crush injury of sciatic nerve in rats. Phytomedicine. 2014; 21(5): 717-723. [CrossRef]
[33] Zhao R, Zhou H, Huang L, Xie Z, Wang J, Gan WB, Yang G. Neuropathic pain causes pyramidal neuronal hyperactivity in the anterior cingulate cortex. Front Cell Neurosci. 2018; 12: 107. [CrossRef]
[34] Caraci F, Merlo S, Drago F, Caruso G, Parenti C, Sortino MA. Rescue of Noradrenergic System as a Novel Pharmacological Strategy in the Treatment of Chronic Pain: Focus on Microglia Activation. Front Pharmacol. 2019; 10: 1024. [CrossRef]
[35] Hayashida KI, Eisenach JC. Spinal α2-adrenoceptor mediated analgesia in neuropathic pain reflects brain derived nerve growth factor and changes in spinal cholinergic neuronal function. Anesthesiology. 2010; 113(2): 406–412. [CrossRef]
[36] Bantel C, Eisenach JC, Duflo F, Tobin JR, Childers SR. Spinal nerve ligation increases alpha2-adrenergic receptor Gprotein coupling in the spinal cord. Brain Res. 2005; 1038(1): 76-82. [CrossRef]
[37] Koga K, Yamada A, Song Q, Li XH, Chen QU, Liu RH, Ge J, Zhan C, Furue H, Zhuo M, Chen T. Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex. Mol Brain. 2020; 13: 49. [CrossRef]
[38] Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017; 18(11): 2483. [CrossRef]
[39] Birder LA, Perl ER. Expression of α2-adrenergic receptors in rat primary afferent neurones after peripheral nerve injury or inflammation. J Physiol. 1999; 515(2): 533–542. [CrossRef]
[40] Austin PJ, Wu A, Moalem-Taylor G. Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats. J Vis Exp. 2012; (61): 3393. [CrossRef]
[41] Tamaddonfard E, Tamaddonfard S, Pourbaba S. Effects of intra-fourth ventricle injection of crocin on capsaicininduced orofacial pain in rats. Avicenna J Phytomed. 2015; 5(5): 450–457.
[42] Kingery WS, Agashe GS, Guo TZ, Sawamura S, Davies MF, Clark JD, Kobilka BK, Maze M. Isoflurane and Nociception: Spinal α2AAdrenoceptors Mediate Antinociception while Supraspinal α1Adrenoceptors Mediate Pronociception. Anesthesiology. 2002; 96(2): 367-374.
[43] Hughes SW, Hickey L, Hulse RP, Lumb BM, Pickering AE. Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury. Pain. 2013; 154(9): 1680-1690. [CrossRef]
[44] Um SW, Kim MJ, Leem JW, Bai SJ, Lee BH. Pain-relieving Effects of mTOR Inhibitor in the Anterior Cingulate Cortex of Neuropathic Rats. Mol Neurobiol. 2019; 56(4): 2482-2494. [CrossRef]
[45] 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. [CrossRef]
[46] 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. [CrossRef]
[47] Akçali D, Belen AD, Babacan A, Bolay H. Nitroglycerin challenge induces lateralized headache in nasociliary nerveligated rats: implications for chronic migraine. Turk J Med Sci. 2017; 47: 681-688. [CrossRef]

Details

Primary Language

English

Subjects

Pharmacology and Pharmaceutical Sciences (Other)

Journal Section

Research Article

Authors

Mohammad Reza Zohrehvand This is me
Iran

Reza Kazemi This is me
Iran

Mohammad Hassan Mirasheh This is me
Iran

Farideh Bahrami This is me
Iran

Mohammad Ali Zabihian This is me
Iran

Gholam Hossein Meftahi This is me
Iran

Mehdi Rahimi-nasrabadi This is me
Iran

Zahra Bahari This is me
Iran

Publication Date

June 27, 2025

Submission Date

January 21, 2020

Acceptance Date

August 10, 2020

Published in Issue

Year 2020 Volume: 24 Number: 6

IZ

https://izlik.org/JA24RG52KU

Cite

RIS / Bibtex

APA

Zohrehvand, M. R., Kazemi, R., Mirasheh, M. H., Bahrami, F., Zabihian, M. A., Meftahi, G. H., Rahimi-nasrabadi, M., & Bahari, Z. (2025). Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats. Journal of Research in Pharmacy, 24(6), 833-841. https://izlik.org/JA24RG52KU

AMA

1.Zohrehvand MR, Kazemi R, Mirasheh MH, et al. Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats. J. Res. Pharm. 2025;24(6):833-841. https://izlik.org/JA24RG52KU

Chicago

Zohrehvand, Mohammad Reza, Reza Kazemi, Mohammad Hassan Mirasheh, et al. 2025. “Crocin Suppressed Cold Allodynia and Anxiety through α2- Adrenoceptors in the Anterior Cingulate Cortex Following Chronic Constriction Injury of Sciatic Nerve in Rats”. Journal of Research in Pharmacy 24 (6): 833-41. https://izlik.org/JA24RG52KU.

EndNote

Zohrehvand MR, Kazemi R, Mirasheh MH, Bahrami F, Zabihian MA, Meftahi GH, Rahimi-nasrabadi M, Bahari Z (June 1, 2025) Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats. Journal of Research in Pharmacy 24 6 833–841.

IEEE

[1]M. R. Zohrehvand et al., “Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats”, J. Res. Pharm., vol. 24, no. 6, pp. 833–841, June 2025, [Online]. Available: https://izlik.org/JA24RG52KU

ISNAD

Zohrehvand, Mohammad Reza - Kazemi, Reza - Mirasheh, Mohammad Hassan - Bahrami, Farideh - Zabihian, Mohammad Ali - Meftahi, Gholam Hossein - Rahimi-nasrabadi, Mehdi - Bahari, Zahra. “Crocin Suppressed Cold Allodynia and Anxiety through α2- Adrenoceptors in the Anterior Cingulate Cortex Following Chronic Constriction Injury of Sciatic Nerve in Rats”. Journal of Research in Pharmacy 24/6 (June 1, 2025): 833-841. https://izlik.org/JA24RG52KU.

JAMA

1.Zohrehvand MR, Kazemi R, Mirasheh MH, Bahrami F, Zabihian MA, Meftahi GH, Rahimi-nasrabadi M, Bahari Z. Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats. J. Res. Pharm. 2025;24:833–841.

MLA

Zohrehvand, Mohammad Reza, et al. “Crocin Suppressed Cold Allodynia and Anxiety through α2- Adrenoceptors in the Anterior Cingulate Cortex Following Chronic Constriction Injury of Sciatic Nerve in Rats”. Journal of Research in Pharmacy, vol. 24, no. 6, June 2025, pp. 833-41, https://izlik.org/JA24RG52KU.

Vancouver

1.Mohammad Reza Zohrehvand, Reza Kazemi, Mohammad Hassan Mirasheh, Farideh Bahrami, Mohammad Ali Zabihian, Gholam Hossein Meftahi, Mehdi Rahimi-nasrabadi, Zahra Bahari. Crocin suppressed cold allodynia and anxiety through α2- adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats. J. Res. Pharm. [Internet]. 2025 Jun. 1;24(6):833-41. Available from: https://izlik.org/JA24RG52KU