Abstract
Evidence shows that the N-methyl-d-aspartate (NMDA) antagonist MK801 reduces the development of morphine (Mor) tolerance. The paraventricular nucleus of the thalamus (PVT) comprises the highest levels of μ-opioid receptors in the thalamus and is involved in pain modulation. The present study examined whether blocking NMDA receptors by administration of MK801 in the PVT nucleus could affect the nociceptive behavioral manifestations caused by the formalin in Mor-dependent rats. Male Wistar rats weighing 250–300 g were dependent on Mor by subcutaneously (s.c.) injection (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. Animals were randomized into four experimental groups in which the NMDA receptor antagonist, MK801 (20 mM in 0.1 ml), or its vehicle were injected into the PVT nucleus for 7 days before each Mor injection. On day 8, the formalin test was carried out. Results showed that repetitive Mor administration prompted antinociception in interphase and phase II of formalin test. Also, inhibition of NMDA receptors decreased formalin-induced nociceptive behaviors in all phases of the test in Mor-dependent rats. Our findings suggested that continuous co-administration of MK801 into PVT with Mor could enhance the antinociceptive effect of Mor and reduce the nociceptive behaviors prompted by formalin in Mor-dependent rats.
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References
Ab Aziz, C. B. and A. H. Ahmad (2006). “The role of the thalamus in modulating pain”. The Malaysian journal of medical sciences: MJMS 13(2): 11.
Babaie, F., M. Kourosh-Arami and M. Farhadi (2022). “Administration of orexin-A into the rat thalamic paraventricular nucleus enhances the naloxone induced morphine withdrawal”. Drug Research 72(04): 209-214.
Bell, J. A. and C. L. Beglan (1995). “Co-treatment with MK-801 potentiates naloxone-predpitated morphine withdrawal in the isolated spinal cord of the neonatal rat”. European journal of pharmacology 294(1): 297-301.
Bennett, G. J. (2000). “Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor”. Journal of pain and symptom management 19(1): 2-6.
Brunton, J. and S. Charpak (1998). “μ-Opioid peptides inhibit thalamic neurons”. Journal of Neuroscience 18(5): 1671-1678.
Buller, A. L., H. C. Larson, B. E. Schneider, J. A. Beaton, R. A. Morrisett and D. T. Monaghan (1994). “The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition”. Journal of Neuroscience 14(9): 5471-5484.
Bullitt, E. (1989). “Induction of c-fos-like protein within the lumbar spinal cord and thalamus of the rat following peripheral stimulation”. Brain research 493(2): 391-397.
Ceccarelli, I., A. Scaramuzzino, C. Massafra and A. M. Aloisi (2003). “The behavioral and neuronal effects induced by repetitive nociceptive stimulation are affected by gonadal hormones in male rats”. Pain 104(1-2): 35-47.
Csaki, A., K. Kocsis, B. Halasz and J. Kiss (2000). “Localization of glutamatergic/aspartatergic neurons projecting to the hypothalamic paraventricular nucleus studied by retrograde transport of [3H] D-aspartate autoradiography”. Neuroscience 101(3): 637-655.
Ding, Y. Q., T. Kaneko, S. Nomura and N. Mizuno (1996). “Immunohistochemical localization of μ-opioid receptors in the central nervous system of the rat”. Journal of Comparative Neurology 367(3): 375-402.
Dougherty, P. M., Y.-J. Li, F. Lenz, L. Rowland and S. Mittman (1996). “Evidence that excitatory amino acids mediate afferent input to the primate somatosensory thalamus”. Brain research 728(2): 267-273.
Erdos, B., Z. Lacza, I. E. Toth, E. Szelke, T. Mersich, K. Komjati, M. Palkovits and P. Sandor (2003). “Mechanisms of pain-induced local cerebral blood flow changes in the rat sensory cortex and thalamus”. Brain research 960(1-2): 219-227.
Garzón, J., M. Rodríguez-Muñoz and P. Sánchez-Blázquez (2008). “Do pharmacological approaches that prevent opioid tolerance target different elements in the same regulatory machinery?” Current drug abuse reviews 1(2): 222-238.
Gutstein, H. B. and K. A. Trujillo (1993). “MK-801 inhibits the development of morphine tolerance at spinal sites”. Brain research 626(1-2): 332-334.
Inturrisi, C. (2005). “The role of N-methyl-D-aspartate (NMDA) receptors in pain and morphine tolerance”. Minerva anestesiologica 71(7-8): 401-403.
Jamero, D., A. Borghol, N. Vo and F. Hawawini (2011). “The emerging role of NMDA antagonists in pain management”. US Pharm 36(5).
Komaki A, S. Shahidi, A. Sarihi, P. Hasanein, R. Lashgari, A. Haghparast, I. Salehi, M. K. Arami (2013). Effects of neonatal C-fiber depletion on interaction between neocortical short-term and long-term plasticity. Basic and clinical neuroscience 4(2): 136.
Kourosh-Arami, M., M. Javan and S. Semnanian (2020). “Inhibition of orexin receptor 1 contributes to the development of morphine dependence via attenuation of cAMP response element-binding protein and phospholipase Cβ3”. Journal of Chemical Neuroanatomy 108: 101801.
Kourosh-Arami, M., M.-T. Joghataei, A. Komaki, M. Gholami, Z. Najafi and M. Lavaie (2021). “Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats”. International Journal of Neuroscience 132(1): 67-76.
Kourosh-Arami, M., A. Komaki and M. Gholami (2022). “Addiction-induced plasticity in underlying neural circuits”. Neurological Sciences 43(3): 1605-1615.
Kourosh-Arami M., M. Soleimani, M. T. Joghataei, F. Mosleh, P. Hayatand A. Komaki (2022). Upregulation of connexins in the rat hippocampal and cortical neurons following blockade of NMDA receptors during postnatal development. Protein and Peptide Letters.
Koyuncuoǧlu, H., Y. Dizdar, F. Aricioǧlu and Ü. Sayin (1992). “Effects of MK 801 on morphine physical dependence: attenuation and intensification”. Pharmacology Biochemistry and Behavior 43(2): 487-490.
Li, Y., S. Li, C. Wei, H. Wang, N. Sui and G. J. Kirouac (2010). “Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats”. Psychopharmacology 212(2): 251-265.
Majidinezhad, M., H. Amirteymouri, S. Karimi-Haghighi, M. Kourosh-Arami and A. Haghparast (2022). “Orexin system in the ventral tegmental area is implicated in the rewarding properties of methamphetamine”. European Journal of Pharmacology 930: 175170.
Malakouti, S. M., M. Kourosh Arami, A. A. R. Sarihi, S. Hajizadeh, G. Behzadi, S. Shahidi, A. R. KOMAKI, B. Heshmatian, and M. Vahabian (2008). “Reversible inactivation and excitation of nucleus raphe magnus can modulate tail blood flow of male wistar rats in response to hypothermia” 237-240.
Manning, B. H., J. Mao, H. Frenk, D. D. Price and D. J. Mayer (1996). “Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance”. Pain 67(1): 79-88.
McDevitt, D. S. and N. M. Graziane (2019). “Timing of morphine administration differentially alters paraventricular thalamic neuron activity”. Eneuro 6(6): e0377-19.
Mendez, I. A. and K. A. Trujillo (2008). “NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats”. Psychopharmacology 196(3): 497-509.
Mobarakeh, J. I., K. Takahashi, S. Sakurada, S. Nishino, H. Watanabe, M. Kato and K. Yanai (2005). “Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin A and B (hypocretin-1 and-2) in mice”. Peptides 26(5): 767-777.
Myers, B., C. M. Dolgas, J. Kasckow, W. E. Cullinan and J. P. Herman (2014). “Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis”. Brain Structure and Function 219(4): 1287-1303.
Paxinos, G. and C. Watson (1998). “A stereotaxic atlas of the rat brain”. New York: Academic.
Rezaei, Z., M. Kourosh-Arami, H. Azizi and S. Semnanian (2020). “Orexin type-1 receptor inhibition in the rat lateral paragigantocellularis nucleus attenuates development of morphine dependence”. Neuroscience Letters 724: 134875.
Salt, T. and S. Eaton (1989). “Function of non-NMDA receptors and NMDA receptors in synaptic responses to natural somatosensory stimulation in the ventrobasal thalamus”. Experimental brain research 77(3): 646-652.
Samani, F. and M. K. Arami (2022). “Repeated administration of orexin into the thalamic paraventricular nucleus inhibits the development of morphine-induced analgesia”. Protein and Peptide Letters 29(1): 57-63.
St-Pierre, J. and P. Bedard (1994). “Intranigral but not intrastriatal microinjection of the NMDA antagonist MK-801 induces contralateral circling in the 6-OHDA rat model”. Brain research 660(2): 255-260.
Uroz, V., L. Prensa and J. M. Giménez-Amaya (2004). “Chemical anatomy of the human paraventricular thalamic nucleus”. Synapse 51(3): 173-185.
Zarmehri, H. A., S. Semnanian, Y. Fathollahi, E. Erami, R. Khakpay, H. Azizi and K. Rohampour (2011). “Intra-periaqueductal gray matter microinjection of orexin-A decreases formalin-induced nociceptive behaviors in adult male rats”. The Journal of Pain 12(2): 280-287.
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This work is supported by the Neuroscience Research Center of the Iran University of Medical Sciences.
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FS, MKA, and MF were responsible for the study concept and design. FS performed the experiments. MKA was responsible for provision of study materials and equipment, study validation, and supervision. MKA and MF assisted with data analysis and interpretation of findings. MKA drafted the manuscript. All authors critically reviewed content and approved final version for publication.
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Samani, F., Arami, M.K. & Farhadi, M. Role of NMDA receptors blockade in the thalamic paraventricular nucleus in morphine dependent rat model of formalin-induced pain. Neurosci Behav Physi 53, 670–677 (2023). https://doi.org/10.1007/s11055-023-01343-6
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DOI: https://doi.org/10.1007/s11055-023-01343-6