Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral µ-opioid receptors

DOI: 10.4236/ojmip.2013.33017   PDF   HTML     3,866 Downloads   5,825 Views   Citations


The systemic administration of morphine affects ventilation via a mixture of central and peripheral actions. The aims of this study were to characterize the ventilatory responses elicited by a low dose of morphine in conscious rats; to determine whether tolerance develops to these responses; and to determine the potential roles of peripheral μ-opioid receptors (μ-ORs) in these responses. Ventilatory parameters were monitored via unrestrained whole-body plethysmography. Conscious male Sprague-Dawley rats received an intravenous injection of vehicle or the peripherally-restricted μ-OR antagonist, naloxone methiodide (NLXmi), and then three successive injections of morphine (1 mg/kg) given 30 min apart. The first injection of morphine in vehicle-treated rats elicited an array of ventilatory excitant (i.e., increases in frequency of breathing, minute volume, respiratory drive, peak inspiratory and expiratory flows, accompanied by decreases in inspiratory time and end inspiratory pause) and inhibitory (i.e., a decrease in tidal volume and an increase in expiratory time) responses. Subsequent injections of morphine elicited progressively and substantially smaller responses. The pattern of ventilatory responses elicited by the first injection of morphine was substantially affected by pretreatment with NLXmi whereas NLXmi minimally affected the development of tolerance to these responses. Low-dose morphine elicits an array of ventilatory excitant and depressant effects in conscious rats that are subject to the development of tolerance. Many of these initial actions of morphine appear to involve activation of peripheral μ-ORs whereas the development of tolerance to these responses does not.

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Henderson Jr., F. , May, W. , Gruber, R. , Young, A. , Palmer, L. , Gaston, B. and Lewis, S. (2013) Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral µ-opioid receptors. Open Journal of Molecular and Integrative Physiology, 3, 111-124. doi: 10.4236/ojmip.2013.33017.

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The authors declare no conflicts of interest.


[1] Oguri, K., Yamada-Mori, I., Shigezane, J., Hirano, T. and Yoshimura, H. (1987) Enhanced binding of morphine and nalorphine to opioid delta receptor by glucuronate and sulfate conjugations at the 6-position. Life Sciences, 41, 1457-1464. doi:10.1016/0024-3205(87)90710-7
[2] Frances, B., Gout, R., Campistron, G., Panconi, E. and Cros, J. (1990) Morphine-6-glucuronide is more μ-selective and potent in analgesic tests than morphine. Progress in Clinical Biological Research, 328, 477-480.
[3] Frances, B., Gout, R., Monsarrat, B., Cros, J. and Zajac, J.M. (1992) Further evidence that morphine-6 beta-glucuronide is a more potent opioid agonist than morphine. Journal of Phrmacology and Experimental Therapeutics, 262, 25-31.
[4] Chen, Z.R., Irvine, R.J., Somogyi, A.A. and Bochner, F. (1991) Mu receptor binding of some commonly used opioids and their metabolites. Life Sciences, 48, 2165-2171. doi:10.1016/0024-3205(91)90150-A
[5] Christensen, C.B. and Reiff, L. (1991) Morphine-6-glucuronide: Receptor binding profile in bovine caudate nucleus. Pharmacology and Toxicology, 68, 151-153. doi:10.1111/j.1600-0773.1991.tb02056.x
[6] Trescot, A.M., Datta, S., Lee, M. and Hansen, H. (2008) Opioid pharmacology. Pain Physician, 11, S133-S153.
[7] Dahan, A., Aarts, L. and Smith, T.W. (2010) Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology, 112, 226-238. doi:10.1097/ALN.0b013e3181c38c25
[8] Yeadon, M. and Kitchen, I. (1989) Opioids and respiration. Progress in Neurobiology, 33, 1-16. doi:10.1016/0301-0082(89)90033-6
[9] Shook, J.E., Watkins, W.D. and Camporesi, E.M. (1990) Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depresssion. American Review of Respiratory Disease, 142, 895-909. doi:10.1164/ajrccm/142.4.895
[10] Young, A.P., Gruber, R.B., Discala, J.F., May, W.J., Palmer, L.A. and Lewis, S.J. (2013) Coactivation of μ- and δ-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite. Respiratory Physiology and Neurobiology, 186, 255-264. doi:10.1016/j.resp.2013.02.028
[11] Campbell, C., Weinger, M.B. and Quinn, M. (1995) Alterations in diaphragm EMG activity during opiate-induced respiratory depression. Respiratory Physiology, 100, 107-117. doi:10.1016/0034-5687(94)00119-K
[12] Kaczyńska, K. and Szereda-Przestaszewska, M. (2005) Involvement of vagal opioid receptors in respiratory effects of morphine in anaesthetized rats. Journal of Physiology and Pharmacology, 56, 195-203.
[13] Niedhart, P., Burgener, M.C., Schweiger, J. and Suter, P.M. (1989) Chest wall rigidity during fentanyl and midazolam-fentanyl induction: Ventilatory and hemodynamic effects. Acta Anaesthesiologica Scandinavia, 33, 1-5. doi:10.1111/j.1399-6576.1989.tb02849.x
[14] Willette, R.N., Barcas, P.P., Krieger, A.J. and Sapru, H.N. (1983) Pulmonary resistance and compliance changes evoked by pulmonary opiate receptor stimulation. European Journal of Pharmacology, 91, 181-188. doi:10.1016/0014-2999(83)90463-6
[15] Willette, R.N., Krieger, A.J. and Sapru, H.N. (1982) Opioids increase laryngeal resistance and motoneuron activeity in the recurrent laryngeal nerve. European Journal of Pharmacology, 80, 57-63. doi:10.1016/0014-2999(82)90177-7
[16] Zhang, Z., Xu, F., Zhang, C. and Liang, X. (2009) Opioid μ-receptors in medullary raphe region affect the hypoxic ventilation in anesthetized rats. Respiratory Physiology and Neurobiology, 168, 281-288. doi:10.1016/j.resp.2009.07.015
[17] McQueen, D.S. and Ribeiro, J.A. (1980) Inhibitory actions of methionine-enkephalin and morphine on the cat carotid chemoreceptors. British Journal of Pharmacology, 71, 297-305.
[18] Zimpfer, M., Beck, A., Mayer, N., Raberger, G. and Steinbereithner, K. (1983) Effects of morphine on the control of the cardiovascular system by the carotid-sinus-reflex and by the carotid chemoreflex. Anaesthesist, 32, 60-66.
[19] Kirby, G.C. and McQueen, D.S. (1986) Characterization of opioid receptors in the cat carotid body involved in chemosensory depression in vivo. British Journal of Pharmacology, 88, 889-898. doi:10.1111/j.1476-5381.1986.tb16263.x
[20] Verborgh, C. and Camu, F. (1990) Post-surgical pain relief with zero-order intravenous infusions of meptazinol and morphine: A double-blind placebo-controlled evaluation of their effects on ventilation. European Journal of Clinical Pharmacology, 38, 437-442. doi:10.1007/BF02336680
[21] Reisine, T. and Pasternak, G. (1995) Opioid analgesics and antagonists. In: Hardman, J.G., Limbird, L.E., Molinoff, P.B., Ruddon, R.W. and Gilman, A.G., Eds., 9th Edition, Goodman and Gilman’s the Pharmacological Basis of Therapeutics, McGraw-Hill, New York, pp. 521-556.
[22] Freye, E. and Latasch, L. (2003) Development of opioid tolerance—Molecular mechanisms and clinical consequences. Anasthesiol Intensivmed Notfallmed Schmerzther, 38, 14-26. doi:10.1055/s-2003-36558
[23] Risdahl, J.M., Chao, C., Murtaugh, M.P., Peterson, P.K. and Molitor, T.W. (1992) Acute and chronic morphine administration in swine. Pharmacology Biochemistry and Behavior, 43, 799-806. doi:10.1016/0091-3057(92)90411-8
[24] Hovav, E. and Weinstock, M. (1987) Temporal factors influencing the development of acute tolerance to opiates. Journal of Pharmacology and Experimental Therapeutics, 242, 251-256.
[25] Bowen, S.R., Carpenter, F.G. and Sowell, J.G. (1979) Ventilatory depression in naive and tolerant rats in relation to plasma morphine concentration. British Journal of Pharmacology, 65, 457-463. doi:10.1111/j.1476-5381.1979.tb07851.x
[26] McGilliard, K.L. and Takemori, A.E. (1978) Alterations in the antagonism by naloxone of morphine-induced respiratory depression and analgesia after morphine pretreatment. Journal of Pharmacology and Experimental Therapeutics, 207, 884-891.
[27] Roerig, S.C., Fujimoto, J.M. and Lange D.G. (1987) Development of tolerance to respiratory depression in morphine- and etorphine-pellet-implanted mice. Brain Research, 400, 278-284. doi:10.1016/0006-8993(87)90627-5
[28] Martin, W.R. and Jasinski, D.R. (1969) Physiological parameters of morphine dependence in mantolerance, early abstinence, protracted abstinence. Journal of Psychiatric Research, 7, 9-17. doi:10.1016/0022-3956(69)90007-7
[29] Paronis, C.A. and Woods, J.H., (1997) Ventilation in morphine-maintained rhesus monkeys. II: Tolerance to the antinociceptive but not the ventilatory effects of morphine. Pharmacology and Experimental Therapeutics, 282, 355-362.
[30] Kishioka, S., Paronis, C.A. and Woods, J.H. (2000) Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys. European Journal of Pharmacology, 398, 121-130. doi:10.1016/S0014-2999(00)00279-X
[31] Ling, G.S., Paul, D., Simantov, R. and Pasternak, G.W. (1989) Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. Life Sciences, 45, 1627-1636. doi:10.1016/0024-3205(89)90272-5
[32] Szeto, H.H., Cheng, P.Y., Dwyer, G., Decena, J.A., Wu, D.L. and Cheng, Y. (1991) Morphine-induced stimulation of fetal breathing: Role of mu 1-receptors and central muscarinic pathways. American Journal of Physiology— Regulatory, Integrative and Comparative Physiology, 261, R344-R350.
[33] Cheng, P.Y., Wu, D., Soong, Y., McCabe, S., Decena, J.A. and Szeto, H.H. (1993) Role of μ1- and δ-opioid receptors in modulation of fetal EEG and respiratory activity. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 265, R433-R438.
[34] Paakkari, P., Paakkari, I., Sirén, A.L. and Feuerstein, G. (1990) Respiratory and locomotor stimulation by low doses of dermorphin, a Mu1 receptor-mediated effect. Journal of Pharmacology and Experimental Therapeutics, 252, 235-240.
[35] Horita, A., Carino, M.A. and Chinn, C. (1989) Fentanyl produces cholinergically-mediated analeptic and EEG arousal effects in rats. Neuropharmacology, 28, 481-486. doi:10.1016/0028-3908(89)90083-X
[36] Kayser, V., Chen, Y.L. and Guilbaud, G. (1991) Behavioural evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in carrageenin-induced hyperalgesic rats. Brain Research, 560, 237-244. doi:10.1016/0006-8993(91)91238-V
[37] Tamaddonfard, E. and Hamzeh-Gooshchi, N. (2010) Effect of crocin on the morphine-induced antinociception in the formalin test in rats. Phytotherapy Research, 24, 410-413. doi:10.1002/ptr.2965
[38] Deviche, P. (1997) Affinity of naloxone and its quarternary analogue for avian central delta and mu opioid receptors. Brain Research, 757, 276-279. doi:10.1016/S0006-8993(97)00298-9
[39] Lewanowitsch, T. and Irvine, R.J. (2003) Naloxone and its quaternary derivative, naloxone methiodide, have differing affinities for mu, delta, and kappa opioid receptors in mouse brain homogenates. Brain Research, 964, 302-305. doi:10.1016/S0006-8993(02)04117-3
[40] Lewanowitsch, T. and Irvine, R.J. (2002) Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal. European Journal of Pharmacology, 445, 61-67. doi:10.1016/S0014-2999(02)01715-6
[41] Lewanowitsch, T., Miller, J.H. and Irvine, R.J. (2006) Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide. Life Sciences, 78, 682-688. doi:10.1016/j.lfs.2005.05.062
[42] He, L., Kim, J., Ou, C., McFadden, W., van Rijn, R.M. and Whistler, J.L. (2009) Methadone antinociception is dependent on peripheral opioid receptors. Journal of Pain, 10, 369-379. doi:10.1016/j.jpain.2008.09.011
[43] Yamamoto, A., Kuyama, S., Kamei, C. and Sugimoto, Y. (2010) Characterization of scratching behavior induced by intradermal administration of morphine and fentanyl in mice. European Journal of Pharmacology, 627, 162-166. doi:10.1016/j.ejphar.2009.10.066
[44] Kanbar, R., Stornetta, R.L., Cash, D.R., Lewis, S.J. and Guyenet, P.G. (2010) Photostimulation of Phox2b medullary neurons activates cardiorespiratory function in conscious rats. American Journal of Respiratory Critical Care Medicine, 182, 1184-1194. doi:10.1164/rccm.201001-0047OC
[45] Laferriere, A., Colin-Durand, J. and Moss, I.R. (2005) Ontogeny of respiratory sensitivity and tolerance to the mu-opioid agonist fentanyl in rat. Develop. Brain Research, 156, 210-217. doi:10.1016/j.devbrainres.2005.03.002
[46] Wallenstein, S., Zucker, C.L. and Fleiss, J.L. (1980) Some statistical methods useful in circulation research. Circulation Research, 47, 1-9. doi:10.1161/01.RES.47.1.1
[47] Stefano, G.B., Kream, R.M. and Esch, T. (2009) Revisiting tolerance from the endogenous morphine perspective. Medical Science Monitor, 15, RA189-RA198.
[48] Drake, C.T., Chavkin, C. and Milner, T.A. (2007) Opioid systems in the dentate gyrus. Progress in Brain Research, 163, 245-263. doi:10.1016/S0079-6123(07)63015-5
[49] Keresztes, A., Borics, A. and Tóth G. (2010) Recent advances in endomorphin engineering. ChemMedChem, 5, 1176-1196. doi:10.1002/cmdc.201000077
[50] Connor, M., Osborne, P.B. and Christie, M.J. (2004) μ-opioid receptor desensitization: Is morphine different? British Journal of Pharmacology, 143, 685-696. doi:10.1038/sj.bjp.0705938
[51] Von Zastrow, M., Svingos, A., Haberstock-Debic, H. and Evans, C. (2003) Regulated endocytosis of opioid receptors: Cellular mechanisms and proposed roles in physiological adaptation to opiate drugs. Current Opinions in Neurobiology, 13, 348-353. doi:10.1016/S0959-4388(03)00069-2
[52] Waldhoer, M., Bartlett, S.E. and Whistler, J.L. (2004) Opioid receptors. Annual Reviews of Biochemistry, 73, 953-990. doi:10.1146/annurev.biochem.73.011303.073940
[53] Bailey, C.P. and Connor, M. (2005) Opioids: Cellular mechanisms of tolerance and physical dependence. Current Opinions in Pharmacology, 5, 60-68. doi:10.1016/j.coph.2004.08.012
[54] Bailey, C.P., Oldfield, S., Llorente, J., Caunt, C.J., Teschemacher, A.G., Roberts, L., McArdle, C.A., Smith, F.L., Dewey, W.L., Kelly, E. and Henderson, G. (2009) Involvement of PKCα and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of μ-opioid receptors in mature brain neurons. British Journal of Pharmacology, 158, 157-164. doi:10.1111/j.1476-5381.2009.00140.x
[55] Salvemini, D. and Neumann, W.L. (2009) Peroxynitrite: A strategic linchpin of opioid analgesic tolerance. Trends in Pharmacological Sciences, 30, 194-202. doi:10.1016/j.tips.2008.12.005
[56] Borison, H.L. (1989) Area postrema: Chemoreceptor circumventricular organ of the medulla oblongata. Progress in Neurobiology, 32, 351-390. doi:10.1016/0301-0082(89)90028-2
[57] Duvernoy, H.M. and Risold, P.Y. (2007) The circumventricular organs: An atlas of comparative anatomy and vascularization. Brain Research Reviews, 56, 119-147. doi:10.1016/j.brainresrev.2007.06.002
[58] Atweh, S.F. and Kuhar, M.J. (1977) Autoradiographic localization of opiate receptors in rat brain. III. The telencephalon. Brain Research, 134, 393-405. doi:10.1016/0006-8993(77)90817-4
[59] Moskowitz, A.S. and Goodman, R.R. (1984) Light microscopic autoradiographic localization of mu and delta opioid binding sites in the mouse central nervous system. Journal of Neuroscience, 4, 1331-1342.
[60] Guan, J.L., Wang, Q.P. and Nakai, Y. (1999) Electron microscopic observation of mu-opioid receptor in the rat area postrema. Peptides, 20, 873-880. doi:10.1016/S0196-9781(99)00075-3
[61] Snyder, S.H. and Pasternak, G.W. (2003) Historical review: Opioid receptors. Trends in Pharmacological Sciences, 24, 198-205. doi:10.1016/S0165-6147(03)00066-X
[62] Bhandari, P., Bingham, S. and Andrews, P.L. (1992) The neuropharmacology of loperamide-induced emesis in the ferret: The role of the area postrema, vagus, opiate and 5-HT3 receptors. Neuropharmacology, 31, 735-742. doi:10.1016/0028-3908(92)90034-M
[63] Mosqueda-Garcia, R., Inagami, T., Appalsamy, M., Sugiura, M. and Robertson, R.M. (1993) Endothelin as a neuropeptide. Cardiovascular effects in the brainstem of normotensive rats. Circulation Research, 72, 20-35. doi:10.1161/01.RES.72.1.20
[64] Fregoneze, J.B. and Antunes-Rodrigues, J. (1992) Role of opioid peptides and subfornical organ in the renal function of intact and hypophysectomized rats. Physiology and Behavior, 51, 287-292. doi:10.1016/0031-9384(92)90142-O
[65] Gatti, P.J., Dias Souza, J., Taveira Da Silva, A.M., Quest, J.A. and Gillis, R.A. (1985) Chemical stimulation of the area postrema induces cardiorespiratory changes in the cat. Brain Research, 346, 115-123. doi:10.1016/0006-8993(85)91100-X
[66] Ferguson, A.V., Beckmann, L.M. and Fisher, J.T. (1989) Effects of subfornical organ stimulation on respiration in the anesthetized rat. Canadian Journal of Physiology and Pharmacology, 67, 1097-1101. doi:10.1139/y89-173
[67] Bodineau, L. and Larnicol, N. (2001) Brainstem and hypothalamic areas activated by tissue hypoxia: Fos-like immunoreactivity induced by carbon monoxide inhalation in the rat. Neuroscience, 108, 643-653. doi:10.1016/S0306-4522(01)00442-0
[68] Sarton, E., Teppema, L. and Dahan, A. (1999) Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop. Anesthesiology, 90, 1329-1338. doi:10.1097/00000542-199905000-00017

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