Cellular and Molecular Neurobiology

, Volume 30, Issue 1, pp 113–121 | Cite as

Spinal and Peripheral Mechanisms Involved in the Enhancement of Morphine Analgesia in Acutely Inflamed Mice

  • Sara González-Rodríguez
  • Agustín Hidalgo
  • Ana Baamonde
  • Luis Menéndez
Original Paper


The analgesic effect induced by opiates is often potentiated during experimental inflammatory processes. We describe here that lower doses of systemic morphine are necessary to increase thermal withdrawal latencies measured in both hind paws of mice acutely inflamed with carrageenan than in healthy ones. This bilateral potentiation seems mediated through spinal opioid receptors since it is inhibited by the intrathecal (i.t.), but not intraplantar ( administration of the opioid receptor antagonist naloxone-methiodide, and also appears when morphine is i.t. administered. Furthermore, the administration of the nitric oxide (NO) synthase inhibitor, l-NMMA, or the K ATP + -channel blocker, glibenclamide, to carrageenan-inflamed mice inhibits the enhanced effect of systemic morphine in the paw that receives the injection of the drug, without affecting the potentiation observed in the contralateral one. The administration of l-NMMA also partially antagonised the analgesic effect induced by i.t. morphine in inflamed mice. Finally, the increased analgesic effect evoked by the administration of the NO donor SIN-1 either in the inflamed or in the contralateral paw of carrageenan-inflamed mice suggests that enhanced responsiveness to the peripheral analgesic effect of NO may be also underlying the bilateral potentiation of morphine-induced analgesia in acutely inflamed mice.


Morphine Thermal hyperalgesia Carrageenan-induced inflammation Nitric oxide Mice 



Grants were provided by MEC-FEDER (SAF2006-05226). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain.


  1. Brock SC, Tonussi CR (2008) Intrathecally injected morphine inhibits inflammatory paw edema: the involvement of nitric oxide and cyclic-guanosine monophosphate. Anesth Analg 106:965–971CrossRefPubMedGoogle Scholar
  2. Curto-Reyes V, Juárez L, García-Pérez E, Fresno MF, Hidalgo A, Menéndez L, Baamonde A (2008) Local loperamide inhibits thermal hyperalgesia but not mechanical allodynia induced by intratibial inoculation of melanoma cells in mice. Cell Mol Neurobiol 28:981–990CrossRefPubMedGoogle Scholar
  3. Fecho K, Manning EL, Maixner W, Schmitt CP (2007) Effects of carrageenan and morphine on acute inflammation and pain in Lewis and Fischer rats. Brain Behav Immun 21:68–78CrossRefPubMedGoogle Scholar
  4. Ferreira SH, Lorenzetti BB (1994) Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception. Neuropharmacology 33:1479–1485CrossRefPubMedGoogle Scholar
  5. Ferreira SH, Duarte ID, Lorenzetti BB (1991) The molecular mechanism of action of peripheral morphine analgesia: stimulation of the cGMP system via nitric oxide release. Eur J Pharmacol 201:121–122CrossRefPubMedGoogle Scholar
  6. Funez MI, Ferrari LF, Duarte DB, Sachs D, Cunha FQ, Lorenzetti BB, Parada CA, Ferreira SH (2008) Inaugural article: teleantagonism: a pharmacodynamic property of the primary nociceptive neuron. Proc Natl Acad Sci USA 105:19038–19043CrossRefPubMedGoogle Scholar
  7. Hassan AH, Ableitner A, Stein C, Herz A (1993) Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 55:185–195CrossRefPubMedGoogle Scholar
  8. Hurley RW, Hammond DL (2000) The analgesic effects of supraspinal mu and delta opioid receptor agonists are potentiated during persistent inflammation. J Neurosci 20:1249–1259PubMedGoogle Scholar
  9. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 17:313–316CrossRefGoogle Scholar
  10. Hylden JL, Thomas DA, Iadarola MJ, Nahin RL, Dubner R (1991) Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia: possible involvement of noradrenergic mechanisms. Eur J Pharmacol 194:135–143CrossRefPubMedGoogle Scholar
  11. Joris J, Costello A, Dubner R, Hargreaves KM (1990) Opiates suppress carrageenan-induced edema and hyperthermia at doses that inhibit hyperalgesia. Pain 43:95–103CrossRefPubMedGoogle Scholar
  12. Kayser V, Guilbaud G (1983) The analgesic effects of morphine, but not those of the enkephalinase inhibitor thiorphan, are enhanced in arthritic rats. Brain Res 267:131–138CrossRefPubMedGoogle Scholar
  13. Luger NM, Sabino MA, Schwei MJ, Mach DB, Pomonis JD, Keyser CP, Rathbun M, Clohisy DR, Honore P, Yaksh TL, Mantyh PW (2002) Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain. Pain 99:397–406CrossRefPubMedGoogle Scholar
  14. Marker CL, Stoffel M, Wickman K (2004) Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. J Neurosci 24:2806–2812CrossRefPubMedGoogle Scholar
  15. Menéndez L, Lastra A, Hidalgo A, Baamonde A (2002) Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. J Neurosci Methods 113:91–97CrossRefPubMedGoogle Scholar
  16. Menéndez L, Juárez L, García V, Hidalgo A, Baamonde A (2007) Involvement of nitric oxide in the inhibition of bone cancer-induced hyperalgesia through the activation of peripheral opioid receptors in mice. Neuropharmacology 53:71–80CrossRefPubMedGoogle Scholar
  17. Millan MJ, Członkowski A, Pilcher CW, Almeida OF, Millan MH, Colpaert FC, Herz A (1987) A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems. J Neurosci 7:77–87PubMedGoogle Scholar
  18. Millan MJ, Członkowski A, Morris B, Stein C, Arendt R, Huber A, Höllt V, Herz A (1988) Inflammation of the hind limb as a model of unilateral, localized pain: influence on multiple opioid systems in the spinal cord of the rat. Pain 35:299–312CrossRefPubMedGoogle Scholar
  19. Parada CA, Vivancos GG, Tambeli CH, Cunha FQ, Ferreira SH (2003) Activation of presynaptic NMDA receptors coupled to NaV1.8-resistant sodium channel C-fibers causes retrograde mechanical nociceptor sensitization. Proc Natl Acad Sci USA 100:2923–2928CrossRefPubMedGoogle Scholar
  20. Perrot S, Guilbaud G, Kayser V (2001) Differential behavioral effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation. Anesthesiology 94:870–875CrossRefPubMedGoogle Scholar
  21. Przewłocka B, Dziedzicka M, Lasoń W, Przewłocki R (1992) Differential effects of opioid receptor agonists on nociception and cAMP level in the spinal cord of monoarthritic rats. Life Sci 50:45–54CrossRefPubMedGoogle Scholar
  22. Przewlocki R, Przewlocka B (2005) Opioids in neuropathic pain. Curr Pharm Des 11:3013–3025CrossRefPubMedGoogle Scholar
  23. Przewłocki R, Przewłocka B (2001) Opioids in chronic pain. Eur J Pharmacol 429:79–91CrossRefPubMedGoogle Scholar
  24. Sachs D, Cunha FQ, Ferreira SH (2004) Peripheral analgesic blockade of hypernociception: activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway. Proc Natl Acad Sci USA 101:3680–3685CrossRefPubMedGoogle Scholar
  25. Shaqura MA, Zöllner C, Mousa SA, Stein C, Schäfer M (2004) Characterization of mu opioid receptor binding and G protein coupling in rat hypothalamus, spinal cord, and primary afferent neurons during inflammatory pain. J Pharmacol Exp Ther 308:712–718CrossRefPubMedGoogle Scholar
  26. Spataro LE, Sloane EM, Milligan ED, Wieseler-Frank J, Schoeniger D, Jekich BM, Barrientos RM, Maier SF, Watkins LR (2004) Spinal gap junctions: potential involvement in pain facilitation. J Pain 5:392–405CrossRefPubMedGoogle Scholar
  27. Stanfa LC, Sullivan AF, Dickenson AH (1992) Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation. Pain 50:345–354CrossRefPubMedGoogle Scholar
  28. Sykes KT, White SR, Hurley RW, Mizoguchi H, Tseng LF, Hammond DL (2007) Mechanisms responsible for the enhanced antinociceptive effects of micro-opioid receptor agonists in the rostral ventromedial medulla of male rats with persistent inflammatory pain. J Pharmacol Exp Ther 322:813–821CrossRefPubMedGoogle Scholar
  29. Vivancos GG, Parada CA, Ferreira SH (2003) Opposite nociceptive effects of the arginine/NO/cGMP pathway stimulation in dermal and subcutaneous tissues. Br J Pharmacol 138:1351–1357CrossRefPubMedGoogle Scholar
  30. Whiteside GT, Boulet JM, Walker K (2005) The role of central and peripheral mu opioid receptors in inflammatory pain and edema: a study using morphine and DiPOA ([8-(3, 3-diphenyl-propyl)-4-oxo-1-phenyl-1, 3, 8-triaza-spiro[4.5]dec-3-yl]-acetic acid). J Pharmacol Exp Ther 314:1234–1240CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Sara González-Rodríguez
    • 1
  • Agustín Hidalgo
    • 1
  • Ana Baamonde
    • 1
  • Luis Menéndez
    • 1
  1. 1.Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA)Universidad de OviedoOviedoSpain

Personalised recommendations