The effect of intra-cerebroventricular injection of insulin on nociception of formalin test in non-diabetic and short-term diabetic rat models

Document Type : Full paper (Original article)


1 Ph.D. Student in Physiology, Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

3 Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran


Pain is a complex process in the central nervous system (CNS). Several factors can alter the pain threshold and insulin is one of them which is produced by the beta cells of pancreas and capable of crossing blood-brain barrier. The aim of this study was to evaluate the effects of intra-cerebroventricular (ICV) injection of insulin on the pain response to formalin in short-term induced diabetic and non-diabetic rats. Sixty-four Sprague-Dawley male rats (280 ± 30 g) were divided into non-diabetic and diabetic groups. Diabetes was induced with streptozotocin (STZ, 60 mg/kg, i.p) for elimination of peripheral insulin. After proving diabetes, insulin (5 mU/animal, 5 μL) was injected to the left lateral cerebral ventricle while equal volume of normal saline was injected in control groups. After 10 min, formalin test was performed. Present study showed that ICV injection of insulin possessed anti-nociceptive effect in non-diabetic rats in formalin test while in diabetic rats, it did not have this effect and even decreased pain threshold partially. In conclusion we showed that ICV injection of insulin in non-diabetic rats, in contrast with diabetic rats, has an anti-nociceptive effect in formalin test. In short-term diabetic rats, ICV injection of insulin was not able to reduce pain response and partially decreased pain threshold.


Akunne, HC and Soliman, KF (1987). The role of opioid receptors in diabetes and hyperglycemia-induced changes in pain threshold in the rat. Psychopharmacology (Berl). 93: 167-172.
Anuradha, K; Hota, D and Pandhi, P (2004). Possible mechanisms of insulin antinociception. Methods Find Exp. Clin. Pharmacol., 26: 5-8.
Banks, WA; Owen, JB and Erickson, MA (2012). Insulin in the brain: there and back again. Pharmacol. Ther., 136: 82-93.
Blazquez, E; Velazquez, E; Hurtado-Carneiro, V and Ruiz-Albusac, JM (2014). Insulin in the brain: its patho-physiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol. (Lausanne), 5: 161-182.
Courteix, C; Bardin, M; Chantelauze, C; Lavarenne, J and Eschalier, A (1994). Study of the sensitivity of the diabetes -induced pain model in rats to a range of analgesics. Pain. 57: 153-160.
Courteix, C; Eschalier, Aand Lavarenne, J (1993). Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain. 53: 81-88.
Deeds, MC; Anderson, JM; Armstrong, AS; Gastineau, DA; Hiddinga, HJ; Jahangir, A; Eberhardt, NL and Kudva, YC (2011). Single dose streptozotocin-induced diabetes: considerations for study design in islet trans-plantation models. Lab Anim., 45: 131-140.
Duarte, AI; Moreira, PI and Oliveira, CR (2012). Insulin in central nervous system: more than just a peripheral hormone. J. Aging Res., 384017: 1-21.
Dubbuisson, D and Dennis, SG (1977). The formalin test: a quantative study of the analgesic effects of morphine, meperidine and brain stem stimulation in rats and cats. Pain. 4: 161-174.
Gerozissis, K (2003). Brain insulin: regulation, mechanisms of action and functions. Cell Mol. Neurobiol., 23: 1-25.
Gheibi, N; Rasolpor, H; Rajaei, F and Jahani Hashemi, H (2009). Effect of oral consumption of magnesium on glucose concentration and formalin test in diabetic rats. Armaghane-Danesh. 12: 50-60.
Gomar, AHA; Mirazi, N and Gomar, M (2014). Anti-nociceptive effect of Brassica juncea on peripheral neuropathy induced by diabetes in rat. AMUJ. 17: 63-70.
Gordon, AE and Meldrum, BS (1970). Effect of insulin on brain 5-hydroxytryptamine and 5-hydroxy-indole-acetic acid of rat. Biochem. Pharmacol., 19: 3042-3044.
Guneli, E; Gumustekin, M and Ates, M (2010). Possible involvement of ghrelin on pain threshold in obesity. Med. Hypotheses. 74: 452-454.
Gupta, G; Azam, M and Baquer, NZ (1992). Effect of experimental diabetes on the catecholamine metabolism in rat brain. J. Neurochem., 58: 95-100.
Ibironke, GS; Saba, OJ and Olopade, FO (2004). Glycemic control and pain threshold in nalloxan diabetic rats. Afr. J. Biomed. Res., 7: 149-151.
Inase, M; Nakahama, H; Otsuki, T and Fang, JZ (1987). Analgesic effects of serotonin microinjection into nucleus raphe magnus and nucleus raphe dorsalis evaluated by the monosodium urate (MSU) tonic pain model in the rat. Brain Res., 426: 205-211.
Iversen, LL; Iversen, SD and Snyder, SH (1977). Drugs, neurotransmitters and behavior. In: Handbook of
. Plenum, New York.
Kolta, MG; Soliman, KF and Williams, BB (1986). Role of 5-hydroxytryptamine in the regulation of brain neuro-peptides in normal and diabetic rat. Horm Res., 23: 112-121.
Laron, Z (2009). Insulin and the brain. Arch. Physiol. Biochem., 115: 112-116.
Lee, JH; Cox, DJ; Mook, DG and McCarty, RC (1990). Effect of hyperglycemia on pain threshold in alloxan-diabetic rats. Pain. 40: 105-107.
Milan, M and Herz, A (1985). The endocrinology of opioids. Int. Rev. Neurobiol., 26: 1-83.
Millan, MJ (2002). Descending control of pain. Prog. Neurobiol., 66: 355-474.
Ohkubo, Y; Nomura, K and Yamaguchi, I (1991). Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound. Eur. J. Pharmacol., 204: 121-125.
Paxinos, G and Watson, C (1977). The rat brain in stereotaxic coordinates. 5th Edn., San Diego, Academic Press. P: 80.
Plum, L; Schubert, M and Bruning, JC (2005). The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab. 16: 59-65.
Raz, I; Hasdai, D; Seltzer, Z and Melmed, RN (1988). Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes. 37: 1253-1259.
Rutledge, LP; Ngong, JM; Kuperberg, JM; Samaan, SS; Soliman, KF and Kolta, MG (2002). Dopaminergic system modulation of nociceptive response in long-term diabetic rats. Pharmacol. Biochem. Behav., 74: 1-9.
Schulingkam, RP; Pagano, TC; Hung, D and Raffa, RB (2000). Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci. Biobehav. Rev., 24: 855-872.
Sewell, RS and Spencer, PS (1977). The role of biogenic amines in the actions of centrally-acting analgesics. Prog. Med. Chem., 14: 249-283.
Silva, L (2010). Central effects of insulin and IGF1 in diabetic neuropathy. MSc Thesis, School of Biologic Sciences, University of Aveiro. PP: 25-30.
Taber, RI and Latranyi, MB (1981). Antagonism of the analgesic effect of opioid and non-opioid agents by p-chlorophenylalanine (PCPA). Eur. J. Pharmacol., 75: 215-222.
Takeshita, N and Yamaguchi, I (1997). Insulin attenuates formalin-induced nociceptive response in mice through a mechanism that is deranged by diabetes mellitus. J. Pharmacol. Exp. Ther., 281: 315-321.
Zhao, WQ and Alkon, DC (2001). Roles of the brain insulin receptor in spatial learning. Mol. Cell Endocrinol., 177: 125-134.
Zhao, WQ; Dou, JT; Liu, QW and Alkon, DC (2002). Evidence for locally produced insulin in the adult rat brain as a neuroactive peptide. 32nd SFN Meeting. Orlando, FL.