Anti-nociceptive effects of oxytocin receptor modulation in healthy volunteers-A randomized, double-blinded, placebo-controlled study

José A Biurrun Manresa, Jürg Schliessbach, Pascal H Vuilleumier, Monika Müller, Frank Musshoff, Ulrike Stamer, Frank Stüber, Lars Arendt-Nielsen, Michele Curatolo, José A Biurrun Manresa, Jürg Schliessbach, Pascal H Vuilleumier, Monika Müller, Frank Musshoff, Ulrike Stamer, Frank Stüber, Lars Arendt-Nielsen, Michele Curatolo

Abstract

Background: There is increasing evidence for oxytocin as a neurotransmitter in spinal nociceptive processes. Hypothalamic oxytocinergic neurons project to the spinal dorsal horn, where they activate GABA-ergic inhibitory interneurons. The present study tested whether the long-acting oxytocin-analogue carbetocin has anti-nociceptive effects in multi-modal experimental pain in humans.

Methods: Twenty-five male volunteers received carbetocin 100 mcg and placebo (0.9% NaCl) on two different sessions in a randomized, double-blinded, cross-over design. Multi-modal quantitative sensory testing (QST) including a model of capsaicin-induced hyperalgesia and allodynia were performed at baseline and at 10, 60 and 120 min after drug administration. QST data were analysed using mixed linear and logistic regression models. Carbetocin plasma concentrations and oxytocin receptor genotypes were quantified and assessed in an exploratory fashion.

Results: An anti-nociceptive effect of carbetocin was observed on intramuscular electrical temporal summation (estimated difference: 1.26 mA, 95% CI 1.01 to 1.56 mA, p = .04) and single-stimulus electrical pain thresholds (estimated difference: 1.21 mA, 95% CI 1.0 to 1.47 mA, p = .05). Furthermore, the area of capsaicin-induced allodynia was reduced after carbetocin compared to placebo (estimated difference: -6.5 cm2 , 95% CI -9.8 to -3.2 cm2 , p < .001).

Conclusions: This study provides evidence of an anti-nociceptive effect of carbetocin on experimental pain in humans.

Significance: This study provides evidence of the anti-nociceptive effect of intravenous administration of the oxytocin agonist carbetocin in healthy male volunteers.

© 2021 European Pain Federation - EFIC®.

References

REFERENCES

    1. Besson, M., Matthey, A., Daali, Y., Poncet, A., Vuillemier, P., Curatolo, M., Zeilhofer, H. U., & Desmeules, J. (2015). GABAergic modulation in central sensitization in humans. Pain, 156(3), 397-404.
    1. Biurrun Manresa, J. A., Fritsche, R., Vuilleumier, P. H., Oehler, C., Mørch, C. D., Arendt-Nielsen, L., Andersen, O. K., & Curatolo, M. (2014). Is the conditioned pain modulation paradigm reliable? A test-retest assessment using the nociceptive withdrawal reflex. PLoS One, 9(6), e100241.
    1. Breton, J. D., Veinante, P., Uhl-Bronner, S., Vergnano, A. M., Freund-Mercier, M. J., Schlichter, R., & Poisbeau, P. (2008). Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition. Molecular Pain, 4, 1744-8069.
    1. Brussaard, A. B., Kits, K. S., & De Vlieger, T. A. (1996). Postsynaptic mechanism of depression of GABAergic synapses by oxytocin in the supraoptic nucleus of immature rat. Journal of Physiology, 497(2), 495-507.
    1. Condés-Lara, M., Rojas-Piloni, G., Martínez-Lorenzana, G., López-Hidalgo, M., & Rodríguez-Jiménez, J. (2009). Hypothalamospinal oxytocinergic antinociception is mediated by GABAergic and opiate neurons that reduce A-delta and C fiber primary afferent excitation of spinal cord cells. Brain Research, 1247, 38-49.
    1. Condés-Lara, M., Rojas-Piloni, G., Martínez-Lorenzana, G., Rodríguez-Jiménez, J., López Hidalgo, M., & Freund-Mercier, M. J. (2006). Paraventricular hypothalamic influences on spinal nociceptive processing. Brain Research, 1081(1), 126-137.
    1. Condés-Lara, M., Zayas-González, H., Manzano-García, A., Córdova-Quiroz, E., Granados-Mortera, J., García-Cuevas, M., Morales-Gómez, J., & González-Hernández, A. (2016). Successful pain management with epidural oxytocin. CNS Neuroscience & Therapeutics, 22(6), 532-534.
    1. De Bonis, M., Torricelli, M., Leoni, L., Berti, P., Ciani, V., Puzzutiello, R., Severi, F. M., & Petraglia, F. (2012). Carbetocin versus oxytocin after caesarean section: Similar efficacy but reduced pain perception in women with high risk of postpartum haemorrhage. Journal of Maternal-Fetal and Neonatal Medicine, 25(6), 732-735.
    1. Eisenach, J. C., Tong, C., & Curry, R. (2015). Phase 1 safety assessment of intrathecal oxytocin. Anesthesiology, 122(2), 407-413.
    1. Gawecka, E., & Rosseland, L. A. (2014). A secondary analysis of a randomized placebo-controlled trial comparing the analgesic effects of oxytocin with carbetocin. Anesthesia & Analgesia, 119(4), 1004.
    1. Gelman, A., & Loken, E. (2014). The garden of forking paths: Why multiple comparisons can be a problem, even when there is no “fishing expedition” or “p-hacking” and the research hypothesis was posited ahead of time. Psychological Bulletin, 140(5), 1272-1280.
    1. Gimpl, G., & Fahrenholz, F. (2001). The oxytocin receptor system: Structure, function, and regulation. Physiological Reviews, 81(2), 629-683.
    1. Gonzalez-Hernandez, A., & Charlet, A. (2018). Oxytocin, GABA, and TRPV1, the Analgesic Triad? Frontiers in Molecular Neuroscience, 11,
    1. González-Hernández, A., Manzano-García, A., Martínez-Lorenzana, G., Tello-García, I. A., Carranza, M., Arámburo, C., & Condés-Lara, M. (2017). Peripheral oxytocin receptors inhibit the nociceptive input signal to spinal dorsal horn wide-dynamic-range neurons. Pain, 158(11), 2117-2128.
    1. González-Hernández, A., Rojas-Piloni, G., & Condés-Lara, M. (2014). Oxytocin and analgesia: Future trends. Trends in Pharmacological Sciences, 35(11), 549-551.
    1. Grewen, K. M., Light, K. C., Mechlin, B., & Girdler, S. S. (2008). Ethnicity is associated with alterations in oxytocin relationships to pain sensitivity in women. Ethnicity and Health, 13(3), 219-241.
    1. Gutkowska, J., Jankowski, M., Mukaddam-Daher, S., & McCann, S. M. (2000). Oxytocin is a cardiovascular hormone. Brazilian Journal of Medical and Biological Research, 33(6), 625-633.
    1. Hilfiger, L., Zhao, Q., Kerspern, D., Inquimbert, P., Andry, V., Goumon, Y., Darbon, P., Hibert, M., & Charlet, A. (2020). A nonpeptide oxytocin receptor agonist for a durable relief of inflammatory pain. Scientific Reports, 10(1), 3017.
    1. Hobo, S., Hayashida, K. I., & Eisenach, J. C. (2012). Oxytocin inhibits the membrane depolarization-induced increase in intracellular calcium in capsaicin sensitive sensory neurons: A peripheral mechanism of analgesic action. Anesthesia and Analgesia, 114(2), 442-449.
    1. Jiang, C. Y., Fujita, T., & Kumamoto, E. (2014). Synaptic modulation and inward current produced by oxytocin in substantia gelatinosa neurons of adult rat spinal cord slices. Journal of Neurophysiology, 111(5), 991-1007.
    1. Jo, Y.-H., Stoeckel, M.-E., Freund-Mercier, M.-J., & Schlichter, R. (1998). Oxytocin modulates glutamatergic synaptic transmission between cultured neonatal spinal cord dorsal horn neurons. The Journal of Neuroscience, 18(7), 2377-2386.
    1. Juif, P.-E., Breton, J.-D., Rajalu, M., Charlet, A., Goumon, Y., & Poisbeau, P. (2013). Long-lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone synthesis which potentiates GABAA receptor-mediated synaptic inhibition. Journal of Neuroscience, 33(42), 16617-16626.
    1. Landau, R., Wong, C. A., Liu, S.-K., McCarthy, R. J., & Blouin, J.-L. (2010). Oxytocin Receptor Gene (OXTR) and Spinal Opioids for Labor and Post-Cesarean Delivery Analgesia. (p. A590). Proceedings of the American Society of Anesthesiologists (ASA) 2010 Annual Meeting
    1. Louvel, D., Delvaux, M., Felez, A., Fioramonti, J., Bueno, L., Lazorthes, Y., & Frexinos, J. (1996). Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome. Gut, 39(5), 741-747.
    1. Munafò, M. R., Nosek, B. A., Bishop, D. V. M., Button, K. S., Chambers, C. D., Percie du Sert, N., Simonsohn, U., Wagenmakers, E., Ware, J. J., & Ioannidis, J. P. A. (2017). A manifesto for reproducible science. Nature Human Behaviour, 1(1), 1-9.
    1. Nersesyan, Y., Demirkhanyan, L., Cabezas-Bratesco, D., Oakes, V., Kusuda, R., Dawson, T., Sun, X., Cao, C., Cohen, A. M., Chelluboina, B., Veeravalli, K. K., Zimmermann, K., Domene, C., Brauchi, S., & Zakharian, E. (2017). Oxytocin modulates nociception as an agonist of pain-sensing TRPV1. Cell Reports, 21(6), 1681-1691.
    1. Ohlsson, B., Truedsson, M., Bengtsson, M., Torstenson, R., Sjolund, K., Bjornsson, E. S., & Simren, M. (2005). Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial. Neurogastroenterology and Motility, 17(5), 697-704.
    1. Paloyelis, Y., Krahé, C., Maltezos, S., Williams, S. C., Howard, M. A., & Fotopoulou, A. (2016). The analgesic effect of oxytocin in humans: A double-blind, placebo-controlled cross-over study using laser-evoked potentials. Journal of Neuroendocrinology, 28(4), 4-7.
    1. Passoni, I., Leonzino, M., Gigliucci, V., Chini, B., & Busnelli, M. (2016). Carbetocin is a functional selective Gq agonist that does not promote oxytocin receptor recycling after inducing β-arrestin-independent internalisation. Journal of Neuroendocrinology, 28(4), 3-8.
    1. Petersson, M. (2002). Cardiovascular effects of oxytocin. Progress in Brain Research, 139, 281-288.
    1. Rash, J. A., Aguirre-Camacho, A., & Campbell, T. S. (2014). Oxytocin and Pain. The Clinical Journal of Pain, 30(5), 453-462.
    1. Rash, J. A., & Campbell, T. S. (2014). The effect of intranasal oxytocin administration on acute cold pressor pain: A placebo-controlled, double-blind, within-participants crossover investigation. Psychosomatic Medicine, 76(6), 422-429.
    1. Robinson, D. A., Wei, F., Wang, G. D., Li, P., Kim, S. J., Vogt, S. K., Muglia, L. J., & Zhuo, M. (2002). Oxytocin mediates stress-induced analgesia in adult mice. The Journal of Physiology, 540(2), 593-606.
    1. Rojas-Piloni, G., López-Hidalgo, M., Martínez-Lorenzana, G., Rodríguez-Jiménez, J., & Condés-Lara, M. (2007). GABA-mediated oxytocinergic inhibition in dorsal horn neurons by hypothalamic paraventricular nucleus stimulation. Brain Research, 1137(1), 69-77.
    1. Rousselot, P., Papadopoulos, G., Merighi, A., Poulain, D. A., & Theodosis, D. T. (1990). Oxytocinergic innervation of the rat spinal cord. An Electron Microscopic Study. Brain Research, 529(1-2), 178-184.
    1. Sandkühler, J. (2009). Models and mechanisms of hyperalgesia and allodynia. Physiological Reviews, 89(2), 707-758.
    1. Schaible, H.-G., & Grubb, B. D. (1993). Afferent and spinal mechanisms of joint pain. Pain, 55(1), 5-54.
    1. Senn, S. (2006). Change from baseline and analysis of covariance revisited. Statistics in Medicine, 25(24), 4334-4344.
    1. Singer, T., Snozzi, R., Bird, G., Petrovic, P., Silani, G., Heinrichs, M., & Dolan, R. J. (2008). Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain. Emotion, 8(6), 781-791.
    1. Vickers, A. J. (2001). The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: A simulation study. BMC Medical Research Methodology, 1(1), 6.
    1. Vuilleumier, P. H., Besson, M., Desmeules, J., Arendt-Nielsen, L., & Curatolo, M. (2013). Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: A randomized placebo-controlled study. PLoS One, 8(3), e43896.
    1. Vuilleumier, P. H., Biurrun Manresa, J. A., Ghamri, Y., Mlekusch, S., Siegenthaler, A., Arendt-Nielsen, L., & Curatolo, M. (2015). Reliability of quantitative sensory tests in a low back pain population. Regional Anesthesia and Pain Medicine, 40(6), 665-673.
    1. Vuilleumier, P. H., Ortner, C. M., Sia, A. T., Blouin, J.-L., & Landau, R. (2013). Genetic variants of oxytocin receptor gene (OXTR), morphine use, acute and persistent pain after cesarean delivery. (p. A1072). Proceedings of the American Society of Anesthesiologists (ASA) 2013 Annual Meeting
    1. Wermter, A.-K., Kamp-Becker, I., Hesse, P., Schulte-Körne, G., Strauch, K., & Remschmidt, H. (2010). Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 153B(2), 629-639.
    1. Wu, S., Jia, M., Ruan, Y., Liu, J., Guo, Y., Shuang, M., Gong, X., Zhang, Y., Yang, X., & Zhang, D. (2005). Positive association of the oxytocin receptor gene (OXTR) with Autism in the Chinese han population. Biological Psychiatry, 58(1), 74-77.
    1. Xin, Q., Bai, B., & Liu, W. (2017). The analgesic effects of oxytocin in the peripheral and central nervous system. Neurochemistry International, 103, 57-64.
    1. Xu, P. F., Fang, M. J., Jin, Y. Z., Wang, L. S., & Lin, D. S. (2017). Effect of oxytocin on the survival of random skin flaps. Oncotarget, 8(54), 92955-92965.
    1. Yang, J. (1994). Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine, 19(8), 867-871.
    1. Zunhammer, M., Geis, S., Busch, V., Greenlee, M. W., & Eichhammer, P. (2015). Effects of intranasal oxytocin on thermal pain in healthy men: A randomized functional magnetic resonance imaging study. Psychosomatic Medicine, 77(2), 156-166.

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