Recurrent antinociception induced by intrathecal or peripheral oxytocin in a neuropathic pain rat model

  • Abimael González-Hernández
  • Antonio Espinosa De Los Monteros-Zuñiga
  • Guadalupe Martínez-Lorenzana
  • Miguel Condés-LaraEmail author
Research Article


The search for new ligands to treat neuropathic pain remains a challenge. Recently, oxytocin has emerged as an interesting molecule modulating nociception at central and peripheral levels, but no attempt has been made to evaluate the effect of recurrent oxytocin administration in neuropathic pain. Using male Wistar rats with spinal nerve ligation, we evaluated the effects of recurrent spinal (1 nmol; given by lumbar puncture) or peripheral (31 nmol; given by intraplantar injection in the ipsilateral paw to spinal nerve ligation) oxytocin administration on pain-like behavior in several nociceptive tests (tactile allodynia and thermal and mechanical hyperalgesia) on different days. Furthermore, we used an electrophysiological approach to analyze the effect of spinal 1 nmol oxytocin on the activity of spinal dorsal horn wide dynamic range cells. In neuropathic rats, spinal or peripheral oxytocin partially restored the nociceptive threshold measured with the von Frey filaments (tactile allodynia), Hargreaves (thermal hyperalgesia) and Randall–Selitto (mechanical hyperalgesia) tests for 12 days. These results agree with electrophysiological data showing that spinal oxytocin diminishes the neuronal firing of the WDR neurons evoked by peripheral stimulation. This effect was associated with a decline in the activity of primary afferent Aδ- and C-fibers. The above findings show that repeated spinal or peripheral oxytocin administration attenuates the pain-like behavior in a well-established model of neuropathic pain. This study provides a basis for addressing the therapeutic relevance of oxytocin in chronic pain conditions.


Pain Neuropathic Oxytocin 



The authors thank Jessica González Norris for proofreading the manuscript. This study was supported by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT-UNAM Mexico) under Grant agreement no. IN200415 to MC-L and Grants no. IA203117 and IA203119 to AG-H. AEM-Z is a Doctoral student from Programa de Doctorado en Ciencias Biomédicas (PDCB-UNAM) and received fellowship from Consejo Nacional de Ciencia y Tecnología (CONACyT-Mexico).

Author contributions

AEM-Z contributed to the acquisition, analysis and interpretation of data and participated in drafting the manuscript. AG-H, GM-L and MC-L contributed to the conception and design of the study; acquisition, analysis and interpretation of data; and participated in drafting the manuscript. All authors participated in a critical review of the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.


  1. Arletti R, Benelli A, Bertolini A (1993) Influence of oxytocin on nociception and morphine antinociception. Neuropeptides 24:125–129CrossRefGoogle Scholar
  2. Boada MD, Gutierrez S, Eisenach JC (2019) Peripheral oxytocin restores light touch and nociceptor sensory afferents towards normal after nerve injury. Pain. Google Scholar
  3. Breton JD, Veinante P, Uhl-Bronner S, Vergnano AM, Freund-Mercier MJ, 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. Mol Pain 4:19CrossRefGoogle Scholar
  4. Brown DC, Perkowski S (1998) Oxytocin content of the cerebrospinal fluid of dogs and its relationship to pain induced by spinal cord compression. Vet Surg 27:607–611CrossRefGoogle Scholar
  5. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63CrossRefGoogle Scholar
  6. Chapman V, Suzuki R, Dickenson AH (1998) Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5-L6. J Physiol 507:881–894CrossRefGoogle Scholar
  7. Chow LH, Chen YH, Wu WC, Chang EP, Huang EYK (2016) Sex difference in oxytocin-induced anti-hyperalgesia at the spinal level in rats with intraplantar carrageenan-induced inflammation. PLoS One 11:0162218Google Scholar
  8. Chow LH, Chen YH, Lai CF, Lin TY, Chen YJ, Kao JH, Huang EY (2018) Sex difference of angiotensin IV-, LVV-hemorphin 7-, and oxytocin-induced antiallodynia at the spinal level in mice with neuropathic pain. Anesth Analg 126:2093–2101CrossRefGoogle Scholar
  9. Chung JM, Kim HK, Chung K (2004) Segmental spinal nerve ligation model of neuropathic pain. In: Luo DZ (ed) Pain research, methods and protocols. Humana Press Inc., Totowa Ney Jersey, pp 35–46CrossRefGoogle Scholar
  10. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C (2017) Neuropathic pain. Nat Rev Dis Primers 3:17002CrossRefGoogle Scholar
  11. Condés-Lara M, Marina-González N, Martínez-Lorenzana G, Luis-Delgado O, Freund-Mercier MJ (2003) Actions of oxytocin and interactions with glutamate on spontaneous and evoked dorsal spinal cord neuronal activities. Brain Res 976:75–81CrossRefGoogle Scholar
  12. Condés-Lara M, Maie IA, Dickenson AH (2005) Oxytocin actions on afferent evoked spinal cord neuronal activities in neuropathic but not in normal rats. Brain Res 1045:124–133CrossRefGoogle Scholar
  13. Condés-Lara M, Rojas-Piloni G, Martínez-Lorenzana G, Rodríguez-Jiménez J, López Hidalgo M, Freund-Mercier MJ (2006) Paraventricular hypothalamic influences on spinal nociceptive processing. Brain Res 1081:126–137CrossRefGoogle Scholar
  14. Condés-Lara M, Rojas-Piloni G, Martínez-Lorenzana G, Rodríguez-Jiménez J (2009) Paraventricular hypothalamic oxytocinergic cells responding to noxious stimulation and projecting to the spinal dorsal horn represent a homeostatic analgesic mechanism. Eur J Neurosci 30:1056–1063CrossRefGoogle Scholar
  15. Condés-Lara M, Rojas-Piloni G, Martínez-Lorenzana G, Diez-Martínez DC, Rodríguez-Jiménez J (2012) Functional interactions between the paraventricular hypothalamic nucleus and raphe magnus. A comparative study of an integrated homeostatic analgesic mechanism. Neuroscience 209:196–207CrossRefGoogle Scholar
  16. Condés-Lara M, Zayas-Gonzalez H, Manzano-García A, Córdova-Quiroz E, Granados-Mortera J, García-Cuevas M, Morales-Gomez J, González-Hernández A (2016) Successful pain management with epidural oxytocin. CNS Neurosci Ther 22:532–534CrossRefGoogle Scholar
  17. Dalmolin GD, Bannister K, Gonçalves L, Sikandar S, Patel R, Cordeiro M, Gomez MV, Ferreira J, Dickenson AH (2017) Effect of the spider toxin TX3-3 on spinal processing of sensory information in naive and neuropathic rats: an in vivo electrophysiological study. Pain Rep 2:e610CrossRefGoogle Scholar
  18. de Araujo AD, Mobli M, Castro J, Harrington AM, Vetter I, Dekan Z, Muttenthaler M, Wan J, Lewis RJ, King GF, Brierley SM, Alewood PF (2014) Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain. Nat Commun 5:3165CrossRefGoogle Scholar
  19. DeLaTorre S, Rojas-Piloni G, Martínez-Lorenzana G, Rodríguez-Jiménez J, Villanueva L, Condés-Lara M (2009) Paraventricular oxytocinergic hypothalamic prevention or interruption of long-term potentiation in dorsal horn nociceptive neurons: electrophysiological and behavioral evidence. Pain 144:320–328CrossRefGoogle Scholar
  20. Deuis JR, Dvorakova LS, Vetter I (2017) Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci 10:284CrossRefGoogle Scholar
  21. Dirig DM, Salami A, Rathbun ML, Ozaki GT, Yaksh TL (1997) Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Meth 76:183–191CrossRefGoogle Scholar
  22. Dixon WJ (1965) The up-and-down method for small samples. J Am Stat Assoc 60:967–978CrossRefGoogle Scholar
  23. Eliava M, Melchior M, Knobloch-Bollmann HS, Wahis J, da Silva Gouveia M, Tang Y, Ciobanu AC, del Rio RT, Roth LC, Althammer F, Chavant V (2016) A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron 89:1291–1304CrossRefGoogle Scholar
  24. Godínez-Chaparro B, Martínez-Lorenzana G, Rodríguez-Jiménez J, Manzano- García A, Rojas-Piloni G, Condes-Lara M, González-Hernández A (2016) The potential role of serotonergic mechanisms in the spinal oxytocin-induced antinociception. Neuropeptides 60:51–60CrossRefGoogle Scholar
  25. González-Hernández A, Rojas-Piloni G, Condés-Lara M (2014) Oxytocin and analgesia: future trends. Trends Pharmacol Sci 35:549–551CrossRefGoogle Scholar
  26. González-Hernández A, Manzano-García A, Martínez-Lorenzana G, Tello-García IA, 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 158:2117–2128CrossRefGoogle Scholar
  27. Hammock EAD, Levitt P (2013) Oxytocin receptor ligand binding in embryonic tissue and postnatal brain development of the C57BL/6 J mouse. Behav Neurosci 7:195Google Scholar
  28. Han Y, Yu LC (2009) Involvement of oxytocin and its receptor in nociceptive modulation in the central nucleus of amygdala of rats. Neurosci Lett 454:101–104CrossRefGoogle Scholar
  29. Han RT, Kim HB, Kim YB, Choi K, Park GY, Lee PR, Lee J, Kim HY, Park CK, Kang Y, Oh SB, Na HS (2018) Oxytocin produces thermal analgesia via vasopressin-1a receptor by modulating TRPV1 and potassium conductance in the dorsal root ganglion neurons. Korean J Physiol Pharmacol 22:173–182CrossRefGoogle Scholar
  30. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88CrossRefGoogle Scholar
  31. Hicks C, Ramos L, Reekie T, Misagh GH, Narlawar R, Kassiou M, McGregor IS (2014) Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats. Br J Pharmacol 171:2868–2887CrossRefGoogle Scholar
  32. Hobo S, Hayashida K, Eisenach JC (2012) Oxytocin inhibits the membrane depolarization-induced increase in intracellular calcium in capsaicin sensitive sensory neurons: a peripheral mechanism of analgesic action. Anesth Analg 114:442–429CrossRefGoogle Scholar
  33. Juif PE, Poisbeau P (2013) Neurohormonal effects of oxytocin and vasopressin receptor agonists on spinal pain processing in male rats. Pain 154:1449–1456CrossRefGoogle Scholar
  34. Juif PE, Breton JD, 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. J Neurosci 33:16617–16626CrossRefGoogle Scholar
  35. Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355–363CrossRefGoogle Scholar
  36. Kubo A, Shinoda M, Katagiri A, Takeda M, Suzuki T, Asaka J, Yeomans DC, Iwata K (2017) Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia. Pain 158:649–659CrossRefGoogle Scholar
  37. Lundeberg T, Meister B, Björkstrand E, Uvnäs-Moberg K (1993) Oxytocin modulates the effects of galanin in carrageenan-induced hyperalgesia in rats. Brain Res 608:181–185CrossRefGoogle Scholar
  38. Madrazo I, Franco-Bourland RE, León-Meza VM, Mena I (1987) Intraventricular somatostatin-14, arginine vasopressin, and oxytocin: analgesic effect in a patient with intractable cancer pain. Appl Neurophysiol 50:427–431Google Scholar
  39. Manzano-García A, González-Hernández A, Tello-García IA, Martínez-Lorenzana G, Condés-Lara M (2018) The role of peripheral vasopressin 1A and oxytocin receptor son the subcutaneous vasopressin antinociceptive effects. Eur J Pain 22:511–526CrossRefGoogle Scholar
  40. Martínez-Lorenzana G, Espinosa-López L, Carranza M, Arámburo C, Paz-Tres C, Rojas-Piloni G, Condés-Lara M (2008) PVN electrical stimulation prolongs withdrawal latencies and releases oxytocin in cerebrospinal fluid, plasma, and spinal cord tissue in intact and neuropathic rats. Pain 140:265–273CrossRefGoogle Scholar
  41. Mazzuca M, Minlebaev M, Shakirzyanova A, Tyzio R, Taccola G, Janackova S, Gataullina S, Ben-Ari Y, Giniatullin R, Khazipov R (2011) Newborn analgesia mediated by oxytocin during delivery. Front Cell Neurosci 5:3CrossRefGoogle Scholar
  42. Mestre C, Pélissier T, Fialip J, Wilcox G, Eschalier A (1994) A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Meth 32:197–200CrossRefGoogle Scholar
  43. Miranda-Cardenas Y, Rojas-Piloni G, Martínez-Lorenzana G, Rodríguez-Jiménez J, López-Hidalgo M, Freund-Mercier MJ, Condés-Lara M (2006) Oxytocin and electrical stimulation of the paraventricular hypothalamic nucleus produce antinociceptive effects that are reversed by an oxytocin antagonist. Pain 122:182–189CrossRefGoogle Scholar
  44. Montoya GJV, Ariza J, Sutachán JJ, Hurtado H (2002) Relationship between functional deficiencies and the contribution of myelin nerve fibers derived from L4, L5, and L6 spinolumbar branches in adult rat sciatic nerve. Exp Neurol 173:266–274CrossRefGoogle Scholar
  45. Moreno-López Y, Martínez-Lorenzana G, Condés-Lara M, Rojas- Piloni G (2013) Identification of oxytocin receptor in the dorsal horn and nociceptive dorsal root ganglion neurons. Neuropeptides 47:117–123CrossRefGoogle Scholar
  46. Nersesyan Y, Demirkhanyan L, Cabezas-Bratesco D, Oakes V, Kusuda R, Dawson T, Sun X, Cao C, Cohen AM, Chelluboina B, Veeravalli KK, Zimmermann K, Domene C, Brauchi S, Zakharian E (2017) Oxytocin modulates nociception as an agonist of pain-sensing TRPV1. Cell Rep 21:1681–1691CrossRefGoogle Scholar
  47. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, San DiegoGoogle Scholar
  48. Petersson M, Wiberg U, Lundeberg T, Uvnäs-Moberg K (2001) Oxytocin decreases carrageenan induced inflammation in rats. Peptides 22:1479–1484CrossRefGoogle Scholar
  49. Randall LO, Selitto JJ (1957) A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Thér 111:409–4019Google Scholar
  50. Rojas-Piloni G, López-Hidalgo M, Martínez-Lorenzana G, Rodríguez-Jiménez J, Condes-Lara M (2007) GABA-mediated oxytocinergic inhibition in dorsal horn neurons by hypothalamic paraventricular nucleus stimulation. Brain Res 1137:69–77CrossRefGoogle Scholar
  51. Rojas-Piloni G, Mejía-Rodríguez R, Martínez-Lorenzana G, Condes-Lara M (2010) Oxytocin, but not vasopressin, modulates nociceptive responses in dorsal horn neurons. Neurosci Lett 476:32–35CrossRefGoogle Scholar
  52. Rojas-Piloni G, Rodríguez-Jiménez J, Martínez-Lorenzana G, Condés-Lara M (2012) Dorsal horn antinociception mediated by the paraventricular hypothalamic nucleus and locus coeruleus: a comparative study. Brain Res 1461:41–50CrossRefGoogle Scholar
  53. Sawchenko PE, Swanson LW (1982) Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol 205:260–272CrossRefGoogle Scholar
  54. Shiraishi T, Onoe M, Kojima T, Sameshima Y, Kageyama T (1995) Effects of hypothalamic paraventricular nucleus: electrical stimulation produce marked analgesia in rats. Neurobiology 3:393–403Google Scholar
  55. Sun W, Zhou Q, Ba X, Feng X, Hu X, Cheng X, Liu T, Guo J, Xiao L, Jiang J, Xiong D, Hao Y, Chen Z, Jiang C (2018) Oxytocin relieves neuropathic pain through GABA release and presynaptic TRPV1 inhibition in spinal cord. Front Mol Neurosci 11:248CrossRefGoogle Scholar
  56. Suzuki R, Kontinen VK, Matthews E, Williams E, Dickenson AH (2000) Enlargement of the receptive field size to low intensity mechanical stimulation in the rat spinal nerve ligation model of neuropathy. J Periph Nerv Syst 5:248CrossRefGoogle Scholar
  57. Tzabazis A, Mechanic J, Miller J, Klukinov M, Pascual C, Manering N, Carson DS, Jacobs A, Qiao Y, Cuellar J, Frey WH II, Jacobs D, Angst M, Yeomans DC (2016) Oxytocin receptor: expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. Cephalalgia 36:943–950CrossRefGoogle Scholar
  58. Uhl-Bronner S, Waltisperger E, Martinez-Lorenzana G, Condes-Lara M, Freund-Mercier MJ (2005) Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat. Neuroscience 135:147–154CrossRefGoogle Scholar
  59. Urch CE, Dickenson AH (2003) In vivo single unit extracellular recordings from spinal cord neurons of rats. Brain Res Protoc 12:26–34CrossRefGoogle Scholar
  60. Walker SC, Trotter PD, Swaney WT, Marshall A, Mcglone FP (2017) C-tactile afferents: cutaneous mediators of oxytocin release during affiliative tactile interactions? Neuropeptides 64:27–38CrossRefGoogle Scholar
  61. Wang JW, Lundeberg T, Yu LC (2003) Antinociceptive role of oxytocin in the nucleus raphe magnus of rats, an involvement of mu-opioid receptor. Regul Pept 115:153–159CrossRefGoogle Scholar
  62. Yaksh TL, Woller SA, Ramachandran R, Sorkin RL (2015) The search for novel analgesics: targets and mechanisms. F100 Prime Rep 7:56Google Scholar
  63. Yang J (1994) Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine 19:867–871CrossRefGoogle Scholar
  64. Yang J, Chen JM, Song CY, Liu WY, Wang G, Wang CH, Lin BC (2006) Through the central V2, not V1 receptors influencing the endogenous opiate peptide system, arginine vasopressin, not oxytocin in the hypothalamic paraventricular nucleus involves in the antinociception in the rat. Brain Res 1069:127–138CrossRefGoogle Scholar
  65. Yang J, Yang Y, Chen JM, Liu WY, Wang CH, Lin BC (2007) Central oxytocin enhances antinociception in the rat. Peptides 28:1113–1119CrossRefGoogle Scholar
  66. Ye GL, Savelieva KV, Vogel P, Baker KB, Mason S, Lanthorn TH, Rajan I (2015) Ligation of mouse L4 and L5 spinal nerves produces robust allodynia without major motor function deficit. Behav Brain Res 276:99–110CrossRefGoogle Scholar
  67. Yekkirala AS, Roberson DP, Bean BP, Woolf CJ (2017) Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov 16:810CrossRefGoogle Scholar
  68. Yu SQ, Lundeberg T, Yu LC (2003) Involvement of oxytocin in spinal antinociception in rats with inflammation. Brain Res 983:13–22CrossRefGoogle Scholar
  69. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de NeurobiologíaUniversidad Nacional Autónoma de MéxicoQuerétaroMexico

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