Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge


This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO2, decreases in pO2 and sO2) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that 1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and 2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depresssant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated.

Share and Cite:

May, W. , Henderson Jr., F. , Gruber, R. , Discala, J. , Young, A. , Bates, J. , Palmer, L. and Lewis, S. (2013) Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge. Open Journal of Molecular and Integrative Physiology, 3, 134-145. doi: 10.4236/ojmip.2013.33019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] 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
[2] Cashman, J.N. and Dolin, S.J. (2004) Respiratory and haemodynamic effects of acute postoperative pain management: Evidence from published data. British Journal of Anaesthesia, 93, 212-223. doi:10.1093/bja/aeh180
[3] 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
[4] Berkenbosch, A., Teppema, L.J., Olievier, C.N. and Dahan, A. (1997) Influences of morphine on the ventilatory response to isocapnic hypoxia. Anesthesiology, 86, 1342-1349. doi:10.1097/00000542-199706000-00016
[5] Dahan, A., Sarton, E., Teppema, L. and Olievier, C. (1998) Sex-related differences in the influence of morphine on ventilatory control in humans. Anesthesiology, 88, 903-913. doi:10.1097/00000542-199804000-00009
[6] 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
[7] Schurig, J.E., Cavanagh, R.L. and Buyniski, J.P. (1978) Effect of butorphanol and morphine on pulmonary mechanics, arterial blood pressure and venous plasma histamine in the anesthetized dog. Archives Internationales de Pharmacodynamie et de Thérapie, 233, 296-304.
[8] 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
[9] 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
[10] Hakim, T.S., Grunstein, M.M. and Michel, R.P. (1992) Opiate action in the pulmonary circulation. Pulmonary Pharmacology, 5, 159-165. doi:10.1016/0952-0600(92)90036-G
[11] Weinger, M.B. and Bednarczyk, J.M. (1994) Atipamezole, an alpha 2 antagonist, augments opiate-induced muscle rigidity in the rat. Pharmacology, Biochemistry and Behavior, 49, 523-529. doi:10.1016/0091-3057(94)90064-7
[12] 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
[13] 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
[14] 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.
[15] McQueen, D.S. and Ribeiro, J.A. (1981) Effects of beta-endorphin, vasoactive intestinal polypeptide and cholecystokinin octapeptide on cat carotid chemoreceptor activity. Quarterly Journal of Experimental Physiology, 66, 273-284.
[16] 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.
[17] 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
[18] Mayer, N., Zimpfer, M., Raberger, G. and Beck, A. (1989) Fentanyl inhibits the canine carotid chemoreceptor reflex. Anesthesia and Analgesia, 69, 756-762. doi:10.1213/00000539-198912000-00012
[19] Peat, S.J., Hanna, M.H., Woodham, M., Knibb, A.A. and Ponte, J. (1991) Morphine-6-glucuronide: Effects on ventilation in normal volunteers. Pain, 45, 101-104. doi:10.1016/0304-3959(91)90170-3
[20] Torda, T.A. (1981) Alveolar-arterial oxygen tension difference: A critical look. Anaesthia and Intensive Care, 9, 326-330.
[21] Stein, P.D., Goldhaber, S.Z. and Henry, J.W. (1995) Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism. Chest, 107, 139-143. doi:10.1378/chest.107.1.139
[22] 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
[23] Young, A.P., Gruber, R.B., Discala, J.F., May, W.J., Palmer, L.A. and Lewis, S.J. (2013) Co-activation 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
[24] Moss, I.R., Brown, K.A. and Laferriere, A. (2006) Recurrent hypoxia in rats during development increases subsequent respiratory sensitivity to fentanyl. Anesthesiology, 105, 715-718. doi:10.1097/00000542-200610000-00017
[25] Fairchild, K.D., Saucerman, J.J., Raynor, L.L., Sivak, J.A., Xiao, Y., Lake, D.E. and Moorman, J.R. (2009) Endotoxin depresses heart rate variability in mice: Cytokine and steroid effects. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 297, R1019-R1027. doi:10.1152/ajpregu.00132.2009
[26] Hayashi, F., Yoshida, A., Fukuda, Y. and Honda, Y. (1982) CO2-ventilatory response of the anesthetized rat by rebreathing technique. Pflugers Archives, 393, 77-82. doi:10.1007/BF00582395
[27] Pauluhn, J. and Thiel, A. (2007) A simple approach to validation of directed-flow nose-only inhalation chambers. Journal of Applied Toxicology, 27, 160-167. doi:10.1002/jat.1188
[28] Bourke, D.L. and Warley, A. (1989) The steadystate and rebreathing methods compared during morphine administration in humans. Journal of Physiology (Lond), 419, 509-517.
[29] Lévy, P., Bonsignore, M.R. and Eckel, J. (2009) Sleep-disordered breathing and metabolic consequences. European Respiratory Journal, 34, 243-260. doi:10.1183/09031936.00166808
[30] Dempsey, J.A., Veasey, S.C., Morgan, B.J. and O’Donnell, C. (2010) Pathophysiology of sleep apnea. Physiology Reviews, 90, 47-112. doi:10.1152/physrev.00043.2008
[31] Fewell, J.E. and Konduri, G.G. (1988) Repeated exposure to rapidly developing hypoxemia influences the interaction between oxygen and carbon dioxide in initiating arousal from sleep in lambs. Pediatric Research, 24, 28-33. doi:10.1203/00006450-198807000-00008
[32] 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
[33] Quock, R.M., Vaughn, L.K., Barlament, J. and Wojcechowskyj, J.A. (1985) Sex and strain differences in morphine-induced temperature effects in WKYs and SHRs. Brain Research Bulletin, 14, 323-326. doi:10.1016/0361-9230(85)90192-3
[34] Jorenby, D.E., Keesey, R.E. and Baker, T.B. (1988) Characterization of morphine’s excitatory effects. Behavioral Neuroscience, 102, 975-985. doi:10.1037/0735-7044.102.6.975
[35] Kaminski, R.P., Forster, H.V., Klein, J.P., Pan, L.G., Bisgard, G.E. and Hamilton, L.H. (1982) Effect of elevated PICO2 on metabolic rate in humans and ponies. Journal of Applied Physiology, 52, 1623-1628.
[36] Whipp, B.J. and Wassermann, K. (1970) Effect of body temperature on the ventilatory response to exercise. Respiratory Physiology, 8, 354-360. doi:10.1016/0034-5687(70)90042-3
[37] Henry, J.G. and Bainton, C.R. (1974) Human core temperature increase as a stimulus to breathing during moderate exercise. Respiratory Physiology, 21, 183-191. doi:10.1016/0034-5687(74)90093-0
[38] Biancardi, V., Da Silva, L.T., Bícego, K.C. and Gargaglioni, L.H. (2010) Role of Locus coeruleus noradrenergic neurons in cardiorespiratory and thermal control during hypoxia. Respiratory Physiology and Neurobiology, 170, 150-156. doi:10.1016/j.resp.2009.12.004
[39] Barros, R.C. and Branco, L.G. (1998) Effect of nitric oxide synthase inhibition on hypercapnia-induced hypothermia and hyperventilation. Journal of Applied Physiology, 85, 967-972.
[40] Mortola, J.P. and Seifert, E.L. (2002) Circadian patterns of breathing. Respiratory Physiology and Neurobiology, 131, 91-100. doi:10.1016/S1569-9048(02)00040-X
[41] Gautier, H., Bonora, M. and Trinh, H.C. (1993) Ventilatory and metabolic responses to cold and CO2 in intact and carotid body-denervated awake rats. Journal of Applied Physiology, 75, 2570-2579.
[42] Popio, K.A., Jackson, D.H., Ross, A.M., Schreiner, B.F. and Yu, P.N. (1978) Hemodynamic and respiratory effects of morphine and butorphanol. Clinical Pharmacology and Therapeutics, 23, 281-287.
[43] Mitaka, C., Sakanishi, N., Tsunoda, Y. and Mishima, Y. (1985) Comparison of hemodynamic effects of morphine, butorphanol, buprenorphine and pentazocine on ICU patients. The Bulletin of Tokyo Medical and Dental University, 32, 31-39.
[44] Rankin, J. and Dempsey, J.A. (1967) Respiratory muscles and the mechanisms of breathing. American Journal of Physical Medicine, 46, 198-244.
[45] Teppema, L.J. and Dahan, A. (2010) The ventilatory response to hypoxia in mammals: Mechanisms, measurement, and analysis. Physiology Reviews, 90, 675-754. doi:10.1152/physrev.00012.2009
[46] Guyenet, P.G., Stornetta, R.L., Abbott, S.B., Depuy, S.D., Fortuna, M.G. and Kanbar, R. (2010) Central CO2-chemoreception and integrated neural mechanisms of cardiovascular and respiratory control. Journal of Applied Physiology, 108, 995-1002. doi:10.1152/japplphysiol.00712.2009
[47] Fortuna, M.G., Stornetta, R. L., West, G.H. and Guyenet, P.G. (2009) Activation of the retrotrapezoid nucleus by posterior hypothalamic stimulation. Journal of Physiology, 587, 5121-5138. doi:10.1113/jphysiol.2009.176875
[48] Bhargava, H.N., Villar, V.M., Gulati, A. and Chari, G. (1991) Analgesic and hyperthermic effects of intravenously administered morphine in the rat are related to its serum levels. Journal of Pharmacology and Experimental Therapeutics, 258, 511-516.
[49] Hasegawa, Y., Kishimoto, S., Shibatani, N., Nomura, H., Ishii, Y., Onishi, M., Inotsume, N., Takeuchi, Y. and Fukushima, S. (2010) The pharmacokinetics of morphine and its glucuronide conjugate in a rat model of streptozotocin-induced diabetes and the expression of MRP2, MRP3 and UGT2B1 in the liver. Journal of Pharmacy and Pharmacology, 62, 310-314. doi:10.1211/jpp.62.03.0004
[50] Christrup, L.L. (1997) Morphine metabolites. Acta Anaesthesiologica Scandinavica, 41, 116-122. doi:10.1111/j.1399-6576.1997.tb04625.x
[51] Zheng, M., McErlane, K.M. and Ong, M.C. (1998) High-performance liquid chromatography-mass spectrometry-mass spectrometry analysis of morphine and morphine metabolites and its application to a pharmacokinetic study in male Sprague-Dawley rats. Journal of Pharmaceutical and Biomedical Analysis, 16, 971-980. doi:10.1016/S0731-7085(97)00094-0
[52] Christensen, C.B. and Jargensen, L.N. (1987) Morphine-6-glucuronide has high affinity for the opioid receptor. Pharmacology and Toxicology, 60, 75-76. doi:10.1111/j.1600-0773.1987.tb01724.x
[53] Pasternak, G.W., Bodnar, R.J., Clark, J.A. and Inturrisi, C.E. (1987) Morphine-6-glucuronide, a potent mu agonist. Life Sciences, 41, 2845-2849. doi:10.1016/0024-3205(87)90431-0
[54] Paul, D., Standifer, K.M., Inturrisi, C.E. and Pasternak, G.W. (1989) Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. Journal of Pharmacology and Experimental Therapeutics, 251, 477-483.
[55] Shimomura, K., Kamata, O., Ueki, S., Ida, S. and Oguri, K. (1971) Analgesic effect of morphine glucuronides. Tohoku Journal of Experimental Medicine, 105, 45-52. doi:10.1620/tjem.105.45
[56] Labella, F.S., Pinsky, C. and Havlicek, V. (1979) Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity. Brain Research, 174, 263-271. doi:10.1016/0006-8993(79)90849-7
[57] Yaksh, T.L., Harty, G.J. and Onofrio, B.M. (1986) High doses of spinal morphine produce a nonopiate receptor mediated hyperesthesia: Clinical and theoretic implications. Anesthesiology, 64, 590-597. doi:10.1097/00000542-198605000-00008
[58] Smith, M.T., Watt, J.A. and Cramond, T. (1990) Morphine-3-glucuronide—A potent antagonist of morphine analgesia. Life Sciences, 47, 579-585. doi:10.1016/0024-3205(90)90619-3
[59] Bartlett, S.E., Cramond, T. and Smith, M.T. (1994) The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist and by midazolam, an antagonist at the benzodiazepine site on the GABAA receptor complex. Life Sciences, 54, 687-694. doi:10.1016/0024-3205(94)00552-4
[60] Kryger, M.H. (2000) Management of obstructive sleep apneahypopnea syndrome: Overview. In: Kryger, M.H., Roth, T., Dement, W.C. and Saunders, W.B., Eds., Principles and Practice of Sleep Medicine, 3rd Edition, Elsevier, Philadelphia, pp. 940-954.
[61] Brown, K.A., Laferriere, A., Lakheeram, I. and Moss, I.R. (2006) Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates. Anesthesiology, 105, 665-669. doi:10.1097/00000542-200610000-00009
[62] Wang, D. and Teichtahl, H. (2007) Opioids, sleep architecture and sleep-disordered breathing. Sleep Medicine Reviews, 11, 35-46. doi:10.1016/j.smrv.2006.03.006
[63] Stain, F., Barjavel, M.J., Sandouk, P., Plotkine, M., Scherrmann, J.M. and Bhargava, H.N. (1995) Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-D-glucuronide in the rat. Journal of Pharmacology and Experimental Therapeutics, 274, 852-857.
[64] Romberg, R., Sarton, E., Teppema, L., Matthes, H.W., Kieffer, B.L. and Dahan, A. (2003) Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice. British Journal of Anaesthesia, 91, 862-870. doi:10.1093/bja/aeg279
[65] Kilpatrick, G.J. and Smith, T.W. (2005) Morphine-6-glucuronide: Actions and mechanisms. Medicinal Research Reviews, 25, 521-544.doi:10.1002/med.20035

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.