Document Type : Original Article


Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran



Several studies have demonstrated that nitric oxide (NO) is involved in hyperalgesia induced by NMDA activity in Morphine tolerance and NO synthase inhibitors can attenuate hyperalgesia in morphine tolerance. In addition, one of the possible mechanisms in morphine tolerance is reduction of GABA inhibitory effect. For this reason, we used GABA agonists (muscimol and baclofen) to investigate the effect of GABA agonists on analgesic effect of morphine and NO level of serum. In this study, experimental rats were divided into 4 groups as follows: 1. Control group, 2. Morphine tolerance group, 3. Morphine tolerance + muscimol, and 4-morphine tolerance + baclofen. To induce morphine tolerance in rats, the animals received 10 mg/kg of morphine sulfate intraperitoneal (ip) once a day for 8 days. In the treatment group, GABA agonist was injected on the 1st, 3rd, 5th, and 8th day before morphine injection. Finally, to evaluate GABA agonists treatment on morphine analgesia and hyperalgesia on the 8th day of the study, thermal hyperalgesia was used to evaluate tolerance and hyperalgesia. Then, NO level of serum was investigated as an important factor in OIH. The results indicated that GABA agonists reduced thermal hyperalgesia in the morphine tolerance group (p


Backonja, M., Glanzman, R.L., 2003. Gabapentin dosing for neuropathic pain: Evidence from randomized, placebo-controlled clinical trials. Clin. Therapeut., 25, 81-104.
Bekhit, M.H., 2010. Opioid-induced hyperalgesia and tolerance. Am. J. Therapeut., 17, 498-510.
Bobeck, E.N., Chen, Q., Morgan, M.M., Ingram, S.L., 2014. Contribution of adenylyl cyclase modulation of pre-and postsynaptic GABA neurotransmission to morphine antinociception and tolerance. Neuropsychopharmacol., 39, 2142.
Bonci, A., Williams, J.T., 1997. Increased probability of GABA release during withdrawal from morphine. J. Neurosci., 17, 796-803.
Dumont, H., Guntz, E., Sosnowski, M., Talla, G., Roman, A., Segers, B., 2007. Opioid‐induced hyperalgesia. Eur. J. Anaesthesiol.,24, 205-207.
Fraser, G.L., Gaudreau, G.A., Clarke, P., Menard, D.P., Perkins, M.N., 2000. Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation. Br. J. Pharmacol., 129, 1668-1672.
Gilron, I., Bailey, J.M., Tu, D., Holden, R.R., Weaver, D.F., Houlden, R.L., 2005. Morphine, gabapentin, or their combination for neuropathic pain. New Engl. J. Med., 352, 1324-1334.
Hill, R., Lyndon, A., Withey, S., Roberts, J., Kershaw, Y., Maclachlan, J., Lingford-Hughes, A., Kelly, E., Bailey, C., Hickman, M., 2016. Ethanol reversal of tolerance to the respiratory depressant effects of morphine. Neuropsychopharmacol., 41, 762.
Ho, K., Loh, H.H., Way, E.L., 1976. Pharmacological manipulation of gamma-aminobutyric acid (GABA) in morphine analgesia, tolerance and physical dependence. Life Sci., 18, 1111-1123.
Hosseini, M., Karami, Z., Janzadenh, A., Jameie, S.B., Haji Mashhadi, Z., Yousefifard, M., Nasirinezhad, F., 2014. The effect of intrathecal administration of muscimol on modulation of neuropathic pain symptoms resulting from spinal cord injury; an experimental study. Emerg., 2, 151-157.
Hunt, S.P., Mantyh, P.W., 2001. The molecular dynamics of pain control. Nat.Rev. Neurosci., 2, 83.
Hwang, J.H., Yaksh, T.L., 1997. The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain, 70, 15-22.
Idänpään-Heikkilä, J.J., Guilbaud, G., 1999. Pharmacological studies on a rat model of trigeminal neuropathic pain: Baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour. Pain, 79, 281-290.
Knott, A.B., Bossy-Wetzel, E., 2009. Nitric oxide in health and disease of the nervous system. Antioxidants & Redox Signaling, 11, 541-553.
Kolesnikov, Y.A., Pick, C.G., Ciszewska, G., Pasternak, G.W., 1993. Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor. Proceedings of the National Academy of Sciences, 90, 5162-5166.
Li, X., Clark, J.D., 2001. Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. Mol. Brain Res., 95, 96-102.
Ma, J., Pan, Z.Z., 2006. Contribution of brainstem GABAA synaptic transmission to morphine analgesic tolerance. Pain, 122, 163-173.
Malmberg, A.B., Yaksh, T.L., 1993. Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain, 54, 291-300.
Manning, B.H., Mao, J., Frenk, H., Price, D.D., Mayer, D.J., 1996. Continuous co-administration of dextromethorphan or MK-801 with morphine: Attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance. Pain, 67, 79-88.
Meller, S., Pechman, P., Gebhart, G., Maves, T., 1992. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neurosci., 50, 7-10.
Quintero, L., Cardenas, R., Suarez-Roca, H., 2011. Stress-induced hyperalgesia is associated with a reduced and delayed GABA inhibitory control that enhances post-synaptic NMDA receptor activation in the spinal cord. Pain, 152, 1909-1922.
Ratajczak-Wrona, W., Jablonska, E., Antonowicz, B., Dziemianczyk, D., Grabowska, S.Z., 2013. Levels of biological markers of nitric oxide in serum of patients with squamous cell carcinoma of the oral cavity. Int. J. Oral Sci., 5, 141.
Renfrey, S., Downton, C., Featherstone, J., 2003. The painful reality. Nature Publishing Group.
Rudd, R.A., Aleshire, N., Zibbell, J.E., Matthew Gladden, R., 2016. Increases in drug and opioid overdose deaths-United States, 2000-2014. Am. J. Transplant., 16, 1323-1327.
Schmidtko, A., Gao, W., König, P., Heine, S., Motterlini, R., Ruth, P., Schlossmann, J., Koesling, D., Niederberger, E., Tegeder, I., 2008. cGMP produced by NO-sensitive guanylyl cyclase essentially contributes to inflammatory and neuropathic pain by using targets different from cGMP-dependent protein kinase I. J. Neurosci., 28, 8568-8576.
Sivam, S., Ho, I., 1983. GABAergic drugs, morphine and morphine tolerance: A study in relation to nociception and gastrointestinal transit in mice. Neuropharmacol., 22, 767-774.
Snyder, S.H., 1992. Nitric oxide: first in a new class of neurotransmitters? Sci., 257, 494-496.
Takahashi, M., Kaneto, H., 1995. Role of GABAergic systems in the development of morphine tolerance in formalin-treated mice. Jap. J. Pharmacol., 68, 207-211.
Tiseo, P.J., Inturrisi, C.E., 1993. Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614. J. Pharmacol. Exp. Therapeut., 264, 1090-1096.
Velayudhan, A., Bellingham, G., Morley-Forster, P., 2014. Opioid-induced hyperalgesia. Cont. Educ. Anaesth. Crit. Care Pain, 14, 125-129.
Zanfirescu, A., Cristea, A.N., Nitulescu, G.M., Velescu, B.S., Gradinaru, D., 2017. Chronic monosodium glutamate administration induced hyperalgesia in mice. Nutr., 10, 1.