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Involvement of Gi/o proteins and GIRK channels in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice

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Abstract

The analgesic efficacy of opiates can be enhanced in inflammatory states due to peripheral and spinal alterations. We describe here that the analgesic effect induced by intrathecal (i.t.) morphine assessed by measuring thermal withdrawal latencies is enhanced in carrageenan-inflamed mice. The spinal µ-opioid receptor (MOR) population is not up-regulated as demonstrated by Western blot assays. In contrast, behavioural experiments show the involvement of changes in transduction mechanisms activated by spinal opioid receptors. The i.t. administration of the nitric oxide (NO) synthase inhibitor l-NMMA (3–30 µg) antagonised with a similar potency and efficacy morphine-induced analgesia in inflamed and non-inflamed mice, discarding that an increase in NO release could be responsible of the enhancement of morphine-induced analgesia. The analgesic effects evoked by the i.t. administration of the direct Gi/o protein activator mastoparan (0.03–10 µg), but not those induced by the N-type calcium channel blocker ω-conotoxin GVIA (3–30 ng), were potentiated in inflamed mice, suggesting that postsynaptic and not presynaptic mechanisms could be involved. Furthermore, the inhibitory effects on morphine-induced analgesia produced by the Gi/o protein inhibitor pertussis toxin (0.1–17 ng) or the G-coupled inwardly rectifying potassium (GIRK) channels inhibitor tertiapin-Q (0.75–750 ng) were greatly enhanced in inflamed mice. These results suggest that differences in the transduction mechanism activated by MOR at postsynaptic level, probably related with GIRK channels activity, could participate in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice.

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References

  • Baamonde A, Curto-Reyes V, Juárez L, Meana A, Hidalgo A, Menéndez L (2007) Antihyperalgesic effects induced by the IL-1 receptor antagonist anakinra and increased IL-1beta levels in inflamed and osteosarcoma-bearing mice. Life Sci 81:673–682

    Article  CAS  PubMed  Google Scholar 

  • Chung KM, Song DK, Suh HW, Lee HH, Kim YH (1994) Effects of intrathecal or intracerebroventricular pre-treatment with pertussis toxin on antinociception induced by beta-endorphin or morphine administered intracerebroventricularly in mice. Naunyn-Schmiedeberg's Arch Pharmacol 349:588–593

    Article  CAS  Google Scholar 

  • Chung HJ, Qian X, Ehlers M, Jan YN, Jan LY (2009) Neuronal activity regulates phosphorylation-dependent surface delivery of G protein-activated inwardly rectifying potassium channels. Proc Natl Acad Sci USA 106:629–634

    Article  CAS  PubMed  Google Scholar 

  • Doupnik CA, Davidson N, Lester HA, Kofuji P (1997) RGS proteins reconstitute the rapid gating kinetics of Gbg-activated inwardly rectifying K1 channels. Proc Natl Acad Sci USA 94:10461–10466

    Article  CAS  PubMed  Google Scholar 

  • 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 21:68–78

    Article  CAS  PubMed  Google Scholar 

  • 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 55:185–195

    Article  CAS  PubMed  Google Scholar 

  • Hoheisel U, Unger T, Mense S (2000) A block of spinal nitric oxide synthesis leads to increased background activity predominantly in nociceptive dorsal horn neurones in the rat. Pain 88:249–257

    Article  CAS  PubMed  Google Scholar 

  • Hurley RW, Hammond DL (2000) The analgesic effects of supraspinal mu and delta opioid receptor agonists are potentiated during persistent inflammation. J Neurosci 20:1249–1259

    CAS  PubMed  Google Scholar 

  • Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 17:313–316

    Article  Google Scholar 

  • 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 194:135–143

    Article  CAS  PubMed  Google Scholar 

  • Iadarola MJ, Brady LS, Draisci G, Dubner R (1988) Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: stimulus specificity, behavioral parameters and opioid receptor binding. Pain 35:313–326

    Article  CAS  PubMed  Google Scholar 

  • Ikeda K, Kobayashi T, Ichikawa T, Usui H, Kumanishi T (1995) Functional couplings of the δ- and the κ-opioid receptors with the G-protein-activated K+ channel. Biochem Biophys Res Commun 208:302–308

    Article  CAS  PubMed  Google Scholar 

  • Ikeda K, Kobayashi T, Kumanishi T, Niki H, Yano R (2000) Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia. Neurosci Res 38:113–116

    Article  CAS  PubMed  Google Scholar 

  • Ippolito DL, Xu M, Bruchas MR, Wickman K, Chavkin C (2005) Tyrosine phosphorylation of K(ir)3.1 in spinal cord is induced by acute inflammation, chronic neuropathic pain, and behavioral stress. J Biol Chem 280:41683–41693

    Article  CAS  PubMed  Google Scholar 

  • Ji RR, Rupp F (1997) Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci 17:1776–1785

    CAS  PubMed  Google Scholar 

  • Ji RR, Zhang Q, Law PY, Low HH, Elde R, Hökfelt T (1995) Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 15:8156–8166

    CAS  PubMed  Google Scholar 

  • Joris J, Costello A, Dubner R, Hargreaves KM (1990) Opiates suppress carrageenan-induced edema and hyperthermia at doses that inhibit hyperalgesia. Pain 43:95–103

    Article  CAS  PubMed  Google Scholar 

  • Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis DE (2000) Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat Cell Biol 2:507–514

    Article  CAS  PubMed  Google Scholar 

  • Kolesnikov YA, Pan YX, Babey AM, Jain S, Wilson R, Pasternak GW (1997) Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: evidence for opposing NO actions on morphine analgesia and tolerance. Proc Natl Acad Sci USA 94:8220–8225

    Article  CAS  PubMed  Google Scholar 

  • Kolesnikov YA, Chereshnev I, Criesta M, Pan YX, Pasternak GW (2009) Opposing actions of neuronal nitric oxide synthase isoforms in formalin-induced pain in mice. Brain Res. doi:10.1016/j.brainres.2009.06.041

    PubMed  Google Scholar 

  • Lam HH, Hanley DF, Trapp BD, Saito S, Raja S, Dawson TM, Yamaguchi H (1996) Induction of spinal cord neuronal nitric oxide synthase (NOS) after formalin injection in the rat hind paw. Neurosci Lett 210:201–204

    Article  CAS  PubMed  Google Scholar 

  • Li X, Clark JD (2001) Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. Brain Res Mol Brain Res 95:96–102

    Article  CAS  PubMed  Google Scholar 

  • Lombard M-C, Weil-Fugazza J, Ries C, Allard M (1999) Unilateral joint inflammation induces bilateral and time-dependent changes in neuropeptide FF binding in the superficial dorsal horn of the rat spinal cord: implication of supraspinal descending systems. Brain Research 816:598–608

    Article  CAS  PubMed  Google Scholar 

  • 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 99:397–406

    Article  CAS  PubMed  Google Scholar 

  • Machelska H, Labuz D, Przewłocki R, Przewłocka B (1997) Inhibition of nitric oxide synthase enhances antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord. J Pharmacol Exp Ther 282:977–984

    CAS  PubMed  Google Scholar 

  • Machelska H, Przewłocki R, Radomski MW, Przewłocka B (1998) Differential effects of intrathecally and intracerebroventricularly administered nitric oxide donors on noxious mechanical and thermal stimulation. Pol J Pharmacol 50:407–415

    CAS  PubMed  Google Scholar 

  • 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 24:2806–2812

    Article  CAS  PubMed  Google Scholar 

  • Marker CL, Luján R, Loh HH, Wickman K (2005) Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. J Neurosci 25:3551–3559

    Article  CAS  PubMed  Google Scholar 

  • Meller ST, Gebhart GF (1994) Spinal mediators of hyperalgesia. Drugs 47(Suppl. 5):10–20

    Article  CAS  PubMed  Google Scholar 

  • Meller ST, Cummings CP, Traub RJ, Gebhart GF (1994) The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat. Neuroscience 60:367–374

    Article  CAS  PubMed  Google Scholar 

  • 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 Meth 113:91–97

    Article  Google Scholar 

  • Moises HC, Rusin KI, Macdonald RL (1994) mu-Opioid receptor-mediated reduction of neuronal calcium current occurs via a G(o)-type GTP-binding protein. J Neurosci 14:3842–3851

    CAS  PubMed  Google Scholar 

  • Müllner C, Vorobiov D, Bera AK, Uezono Y, Yakubovich D, Frohnwieser-Steinecker B, Dascal N, Schreibmayer W (2000) Heterologous facilitation of G protein-activated K(+) channels by beta-adrenergic stimulation via cAMP-dependent protein kinase. J Gen Physiol 115:547–558

    Article  PubMed  Google Scholar 

  • Neugebauer V, Vanegas H, Nebe J, Rümenapp P, Schaible HG (1996) Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint. J Neurophysiol 76:3740–3749

    CAS  PubMed  Google Scholar 

  • Ocaña M, Cendán CM, Cobos EJ, Entrena JM, Baeyens JM (2004) Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol 500:203–219

    Article  PubMed  Google Scholar 

  • Odagaki Y, Nishi N, Koyama T (1998) Receptor-mediated and receptor-independent activation of G-proteins in rat brain membranes. Life Sci 62:1537–1541

    Article  CAS  PubMed  Google Scholar 

  • Osborne MG, Coderre TJ (1999) Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan-induced thermal hyperalgesia. Br J Pharmacol 126:1840–1846

    Article  CAS  PubMed  Google Scholar 

  • Ossipov MH, Kovelowski CJ, Porreca F (1995) The increase in morphine antinociceptive potency produced by carrageenan-induced hindpaw inflammation is blocked by naltrindole, a selective delta-opioid antagonist. Neurosci Lett 184:173–176

    Article  CAS  PubMed  Google Scholar 

  • Pan HL, Wu ZZ, Zhou HY, Chen SR, Zhang HM, Li DP (2008) Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Therap 117:141–161

    Article  CAS  Google Scholar 

  • 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 94:870–875

    Article  CAS  PubMed  Google Scholar 

  • 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 50:45–54

    Article  PubMed  Google Scholar 

  • Przewlocki R, Przewlocka B (2005) Opioids in neuropathic pain. Curr Pharm Des 11:3013–3025

    Article  CAS  PubMed  Google Scholar 

  • Przewłocki R, Machelska H, Przewłocka B (1993) Inhibition of nitric oxide synthase enhances morphine antinociception in the rat spinal cord. Life Sci 53:PL1–PL5

    Article  PubMed  Google Scholar 

  • Sadja R, Alagem N, Reuveny E (2003) Gating of GIRK channels: details of an intricate, membrane-delimited signalling complex. Neuron 39:9–12

    Article  CAS  PubMed  Google Scholar 

  • Saitoh O, Kubo Y, Odagiri M, Ichikawa M, Yamagata K, Sekine T (1999) RGS7 and RGS8 differentially accelerate G protein-mediated modulation of K+ currents. J Biol Chem 274:9899–9904

    Article  CAS  PubMed  Google Scholar 

  • Schroeder CI, Doering CJ, Zamponi GW, Lewis RJ (2006) N-type calcium channel blockers: novel therapeutics for the treatment of pain. Med Chem 2:535–543

    Article  CAS  PubMed  Google Scholar 

  • Seelbach MJ, Brooks TA, Egleton RD, Davis TP (2007) Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein. J Neurochem 102:1677–1690

    Article  CAS  PubMed  Google Scholar 

  • 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 308:712–718

    Article  CAS  PubMed  Google Scholar 

  • Solodkin A, Traub RJ, Gebhart GF (1992) Unilateral hindpaw inflammation produces a bilateral increase in NADPH-diaphorase histochemical staining in the rat lumbar spinal cord. Neuroscience 51:495–499

    Article  CAS  PubMed  Google Scholar 

  • Song HK, Pan HL, Eisenach JC (1998) Spinal nitric oxide mediates antinociception from intravenous morphine. Anesthesiology 89:215–221

    Article  CAS  PubMed  Google Scholar 

  • Sousa AM, Prado WA (2001) The dual effect of a nitric oxide donor in nociception. Brain Res 897:9–19

    Article  CAS  PubMed  Google Scholar 

  • Stanfa LC, Dickenson AH (1993) Cholecystokinin as a factor in the enhanced potency of spinal morphine following carrageenin inflammation. Br J Pharmacol 108:967–973

    CAS  PubMed  Google Scholar 

  • Svendsen F, Rygh LJ, Hole K, Tjølsen A (1999) Dorsal horn NMDA receptor function is changed after peripheral inflammation. Pain 83:517–523

    Article  CAS  PubMed  Google Scholar 

  • 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 322:813–821

    Article  CAS  PubMed  Google Scholar 

  • Terenghi G, Riveros-Moreno V, Hudson LD, Ibrahim NB, Polak JM (1993) Immunohistochemistry of nitric oxide synthase demonstrates immunoreactive neurons in spinal cord and dorsal root ganglia of man and rat. J Neurol Sci 118:34–37

    Article  CAS  PubMed  Google Scholar 

  • Traub RJ, Solodkin A, Meller ST, Gebhart GF (1994) Spinal cord NADPH-diaphorase histochemical staining but not nitric oxide synthase immunoreactivity increases following carrageenan-produced hindpaw inflammation in the rat. Brain Res 668:204–210

    Article  CAS  PubMed  Google Scholar 

  • Tseng LF, Collins KA (1995) Pretreatment with pertussis toxin blocks morphine- but not β-endorphin-induced antinociception in the mouse. Eur J Pharmacol 294:345–348

    Article  CAS  PubMed  Google Scholar 

  • Walczak JS, Pichette V, Leblond F, Desbiens K, Beaulieu P (2005) Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain. Neuroscience 132:1093–1102

    Article  CAS  PubMed  Google Scholar 

  • 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 314:1234–1240

    Article  CAS  PubMed  Google Scholar 

  • Wu ZZ, Chen SR, Pan HL (2004) Differential sensitivity of N- and P/Q-type Ca2+ channel currents to a mu opioid in isolectin B4-positive and -negative dorsal root ganglion neurons. J Pharmacol Exp Ther 311:939–947

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Tong C, Pan HL, Cerda SE, Eisenach JC (1997) Intravenous morphine increases release of nitric oxide from spinal cord by an alpha-adrenergic and cholinergic mechanism. J Neurophysiol 78:2072–2078

    CAS  PubMed  Google Scholar 

  • Yamamoto J, Kawamata T, Niiyama Y, Omote K, Namiki A (2008) Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain. Neuroscience 151:843–853

    Article  CAS  PubMed  Google Scholar 

  • Yang HY, Tao T, Iadarola MJ (2008) Modulatory role of neuropeptide FF system in nociception and opiate analgesia. Neuropeptides 42:1–18

    Article  PubMed  Google Scholar 

  • Zeidner G, Sadja R, Reuveny E (2001) Redox-dependent gating of G protein-coupled inwardly rectifying K+ channels. Biol Chem 276:35564–35570

    Article  CAS  Google Scholar 

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Acknowledgments

Grants were provided by MEC-FEDER (SAF2009-10567). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain.

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The authors declare that they have no conflict of interest.

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  1. Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006, Oviedo, Asturias, Spain

    Sara González-Rodríguez, Agustín Hidalgo, Ana Baamonde & Luis Menéndez

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  1. Sara González-Rodríguez
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  2. Agustín Hidalgo
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  3. Ana Baamonde
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  4. Luis Menéndez
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Correspondence to Luis Menéndez.

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González-Rodríguez, S., Hidalgo, A., Baamonde, A. et al. Involvement of Gi/o proteins and GIRK channels in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice. Naunyn-Schmied Arch Pharmacol 381, 59–71 (2010). https://doi.org/10.1007/s00210-009-0471-3

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