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Reduced Number, G Protein Coupling, and Antinociceptive Efficacy of Spinal Mu-Opioid Receptors in Diabetic Rats Are Reversed by Nerve Growth Factor

      Abstract

      This study investigated putative mechanisms of impaired spinal opioid antinociception such as a downregulation of mu-opioid receptor (MOR) number, coupling, and efficacy in rats with advanced (12 weeks) streptozotocin (STZ)-induced diabetes. Intravenous injection of STZ (45 mg/kg) in Wistar rats led to selective degeneration of insulin-producing pancreatic ß-cells, elevated blood glucose, and mechanical hyperalgesia. In these animals, dose-dependent and naloxone-reversible intrathecal fentanyl antinociception was significantly impaired and associated with a loss in MOR immunoreactivity of calcitonin gene-related peptide–immunoreactive (CGRP-IR) sensory nerve terminals, membrane-bound MOR binding sites, and MOR-stimulated G protein coupling within the dorsal horn of the spinal cord. Intrathecal delivery of nerve growth factor (NGF) in diabetic animals normalized spinal MOR number and G protein coupling and rescued spinal fentanyl-induced antinociception. These findings identify for the first time a loss in functional MOR on central terminals of sensory neurons as a contributing factor for the impaired spinal opioid responsiveness during advanced STZ-induced diabetes that can be reversed by NGF. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (eg, arthritis, cancer, neuropathy) and may give novel therapeutic incentives.

      Perspective

      In diabetic neuropathy a loss in sensory neuron mu-opioid receptor number and coupling contributes to impaired spinal opioid antinociception that can be reversed by NGF. These findings support growing evidence of a distinct regulation of opioid responsiveness during various painful diseases and may give novel therapeutic incentives.

      Key words

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      References

        • Abbadie C.
        • Lombard M.C.
        • Besson J.M.
        • Trafton J.A.
        • Basbaum A.I.
        Mu and delta opioid receptor-like immunoreactivity in the cervical spinal cord of the rat after dorsal rhizotomy or neonatal capsaicin: An analysis of pre- and postsynaptic receptor distributions.
        Brain Res. 2002; 15: 150-162
        • Abbadie C.
        • Pasternak G.W.
        • Aicher S.A.
        Presynaptic localization of the carboxy-terminus epitopes of the mu opioid receptor splice variants MOR-1C and MOR-1D in the superficial laminae of the rat spinal cord.
        Neuroscience. 2001; 106: 833-842
        • Aimone L.D.
        • Yaksh T.L.
        Opioid modulation of capsaicin-evoked release of substance P from rat spinal cord in vivo.
        Peptides. 1989; 10: 1127-1131
        • Arvidsson U.
        • Riedl M.
        • Chakrabarti S.
        • Lee J.H.
        • Nakano A.H.
        • Dado R.J.
        • Loh H.H.
        • Law P.Y.
        • Wessendorf M.W.
        • Elde R.
        Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord.
        J Neurosci. 1995; 15: 3328-3341
        • Bitar M.S.
        • Pilcher C.W.
        Attenuation of IGF-1 antinociceptive action and a reduction in spinal cord gene expression of its receptor in experimental diabetes.
        Pain. 1998; 75: 69-74
        • Bourgoin S.
        • Benoliel J.J.
        • Collin E.
        • Mauborgne A.
        • Pohl M.
        • Hamon M.
        • Cesselin F.
        Opioidergic control of the spinal release of neuropeptides: Possible significance for the analgesic effects of opioids.
        Fund Clin Pharmacol. 1994; 8: 307-321
        • Cahill C.M.
        • Dray A.
        • Coderre T.J.
        Intrathecal nerve growth factor restores opioid effectiveness in an animal model of neuropathic pain.
        Neuropharmacology. 2003; 45: 543-552
        • Calcutt N.A.
        • Jorge M.C.
        • Yaksh T.L.
        • Chaplan S.R.
        Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: Effects of insulin, aldose reductase inhibition and lidocaine.
        Pain. 1996; 68: 293-299
        • Chen S.R.
        • Pan H.L.
        Antinociceptive effect of morphine, but not mu opioid receptor number, is attenuated in the spinal cord of diabetic rats.
        Anesthesiology. 2003; 99: 1409-1414
        • Chen S.R.
        • Sweigart K.L.
        • Lakoski J.M.
        • Pan H.L.
        Functional mu opioid receptors are reduced in the spinal cord dorsal horn of diabetic rats.
        Anesthesiology. 2002; 97: 1602-1608
        • Comelli F.
        • Bettoni I.
        • Colombo A.
        • Fumagalli P.
        • Giagnoni G.
        • Costa B.
        Rimonabant, a cannabinoid CB1 receptor antagonist, attenuates mechanical allodynia and counteracts oxidative stress and nerve growth factor deficit in diabetic mice.
        Eur J Pharmacol. 2010; 637: 62-69
        • Courteix C.
        • Bourget P.
        • Caussade F.
        • Bardin M.
        • Coudore F.
        • Fialip J.
        • Eschalier A.
        Is the reduced efficacy of morphine in diabetic rats caused by alterations of opiate receptors or of morphine pharmacokinetics?.
        J Pharmacol Exp Ther. 1998; 285: 63-70
        • Fressinaud C.
        • Jean I.
        • Dubas F.
        Selective decrease in axonal nerve growth factor and insulin-like growth factor I immunoreactivity in axonopathies of unknown etiology.
        Acta Neuropathol. 2003; 105: 477-483
        • Gehling M.
        • Tryba M.
        Risks and side effects of intrathecal morphine combined with spinal anesthesia: A meta-analysis.
        Anaesthesia. 2009; 64: 643-651
        • Gouardères C.
        • Beaudet A.
        • Zajac J.M.
        • Cros J.
        • Quirion R.
        High resolution radioautographic localization of [125I]FK-33-824-labelled mu opioid receptors in the spinal cord of normal and deafferented rats.
        Neuroscience. 1991; 43: 197-209
        • Hajializadeh Z.
        • Esmaeili-Mahani S.
        • Sheibani V.
        • Kaeidi A.
        • Atapour M.
        • Abbasnejad M.
        Changes in the gene expression of specific G-protein subunits correlate with morphine insensitivity in streptozotocin-induced diabetic rats.
        Neuropeptides. 2010; 44: 299-304
        • Hall K.E.
        • Liu J.
        • Sima A.A.
        • Wiley J.W.
        Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy.
        J Neurophysiol. 2001; 86: 760-770
        • Hayek S.M.
        • Deer T.R.
        • Pope J.E.
        • Panchal S.J.
        • Patel V.B.
        Intrathecal therapy for cancer and non-cancer pain.
        Pain Physician. 2011; 14: 219-248
        • Heinke B.
        • Gingl E.
        • Sandkühler J.
        Multiple targets of μ-opioid receptor-mediated presynaptic inhibition at primary afferent Aδ- and C-fibers.
        J Neurosci. 2011; 31: 1313-1322
        • Hellweg R.
        • Raivich G.
        • Hartung H.D.
        • Hock C.
        • Kreutzberg G.W.
        Axonal transport of endogenous nerve growth factor (NGF) and NGF receptor in experimental diabetic neuropathy.
        Exp Neurol. 1994; 130: 24-30
        • Ikoma M.
        • Kohno T.
        • Baba H.
        Differential presynaptic effects of opioid agonists on Adelta- and C-afferent glutamatergic transmission to the spinal dorsal horn.
        Anesthesiology. 2007; 107: 807-812
        • Ji R.R.
        • Zhang Q.
        • Law P.Y.
        • Low H.H.
        • Elde R.
        • Hökfelt T.
        Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation.
        J Neurosci. 1995; 15: 8156-8166
        • Kanbayashi H.
        • Itoh H.
        • Kashiwaya T.
        • Atoh K.
        • Makino I.
        Spatial distribution of nociceptive neuropeptide and nerve growth factor depletion in experimental diabetic peripheral nervous system.
        J Int Med Res. 2002; 30: 512-519
        • Kohno T.
        • Kumamoto E.
        • Higashi H.
        • Shimoji K.
        • Yoshimura M.
        Actions of opioids on excitatory and inhibitory transmission in substantia gelatinosa of adult rat spinal cord.
        J Physiol. 1999; 518: 803-813
        • Liu E.H.
        • Li C.
        • Govindasamy M.
        • Neo H.J.
        • Lee T.L.
        • Low C.M.
        • Tachibana S.
        1. Elevated prepro-nociceptin, nociceptin/orphanin FQ and nocistatin concentrations in rat chronic constriction nerve injury and diabetic neuropathic pain models.
        Neurosci Lett. 2012; 506: 104-106
        • Luttrell L.M.
        Transmembrane signaling by G protein-coupled receptors.
        Methods Mol Biol. 2006; 332 (Review): 3-49
        • Molliver D.C.
        • Lindsay J.
        • Albers K.M.
        • Davis B.M.
        Overexpression of NGF or GDNF alters transcriptional plasticity evoked by inflammation.
        Pain. 2005; 113: 277-284
        • Mousa S.A.
        • Cheppudira B.P.
        • Shaqura M.
        • Fischer O.
        • Hofmann J.
        • Hellweg R.
        • Schäfer M.
        Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain.
        Brain. 2007; 130: 502-513
        • Mousa S.A.
        • Shaqura M.
        • Schäper J.
        • Huang W.
        • Treskatsch S.
        • Habazettl H.
        • Abdul-Khaliq H.
        • Schäfer M.
        Identification of mu- and kappa-opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia.
        J Comp Neurol. 2010; 518: 3836-3847
        • Pohl M.
        • Lombard M.C.
        • Bourgoin S.
        • Carayon A.
        • Benoliel J.J.
        • Mauborgne A.
        • Besson J.M.
        • Hamon M.
        • Cesselin F.
        Opioid control of the in vitro release of calcitonin gene-related peptide from primary afferent fibres projecting in the rat cervical cord.
        Neuropeptides. 1989; 14: 151-159
        • Sasaki K.
        • Chancellor M.B.
        • Phelan M.W.
        • Yokoyama T.
        • Fraser M.O.
        • Seki S.
        • Kubo K.
        • Kumon H.
        • Groat W.C.
        • Yoshimura N.
        Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia.
        J Urol. 2002; 168: 1259-1264
        • Scherrer G.
        • Imamachi N.
        • Cao Y.Q.
        • Contet C.
        • Mennicken F.
        • O'Donnell D.
        • Kieffer B.L.
        • Basbaum A.I.
        Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.
        Cell. 2009; 137: 1148-1159
        • Schug S.A.
        • Saunders D.
        • Kurowski I.
        • Paech M.J.
        Neuraxial drug administration: A review of treatment options for anaesthesia and analgesia.
        CNS Drugs. 2006; 11: 917-933
        • Shaqura M.A.
        • Zöllner C.
        • Mousa S.A.
        • Stein C.
        • Schäfer M.
        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. 2004; 308: 712-718
        • Takasusuki T.
        • Yaksh T.L.
        Regulation of spinal substance p release by intrathecal calcium channel blockade.
        Anesthesiology. 2011; 115: 153-164
        • Wang H.B.
        • Zhao B.
        • Zhong Y.Q.
        • Li K.C.
        • Li Z.Y.
        • Wang Q.
        • Lu Y.J.
        • Zhang Z.N.
        • He S.Q.
        • Zheng H.C.
        • Wu S.X.
        • Hökfelt T.G.
        • Bao L.
        • Zhang X.
        Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons.
        Proc Natl Acad Sci USA. 2010; 107: 13117-13122
        • Yaksh T.L.
        • Rudy T.A.
        Analgesia mediated by a direct spinal action of narcotics.
        Science. 1976; 192: 1357-1358
        • Yaksh T.L.
        A drug has to do what a drug has to do.
        Anesth Analg. 1999; 89: 1075-1077
        • Yamdeu R.S.
        • Shaqura M.
        • Mousa S.A.
        • Schäfer M.
        • Droese J.
        p38 Mitogen-activated protein kinase activation by nerve growth factor in primary sensory neurons upregulates μ-opioid receptors to enhance opioid responsiveness toward better pain control.
        Anesthesiology. 2011; 114: 150-161
        • Yiangou Y.
        • Facer P.
        • Sinicropi D.V.
        • Boucher T.J.
        • Bennett D.L.
        • McMahon S.B.
        • Anand P.
        Molecular forms of NGF in human and rat neuropathic tissues: Decreased NGF precursor-like immunoreactivity in human diabetic skin.
        J Peripher Nerv Syst. 2002; 7: 190-197
        • Zhang X.
        • de Araujo Lucas G.
        • Elde R.
        • Wiesenfeld-Hallin Z.
        • Hökfelt T.
        Effect of morphine on cholecystokinin and mu-opioid receptor-like immunoreactivities in rat spinal dorsal horn neurons after peripheral axotomy and inflammation.
        Neuroscience. 2000; 95: 197-207
        • Zöllner C.
        • Shaqura M.A.
        • Bopaiah C.P.
        • Mousa S.
        • Stein C.
        • Schafer M.
        Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons.
        Mol Pharmacol. 2003; 64: 202-210
        • Zurek J.R.
        • Nadeson R.
        • Goodchild C.S.
        Spinal and supraspinal components of opioid antinociception in streptozotocin induced diabetic neuropathy in rats.
        Pain. 2001; 90: 57-63
        • Zwick M.
        • Molliver D.C.
        • Lindsay J.
        • Fairbanks C.A.
        • Sengoku T.
        • Albers K.M.
        • Davis B.M.
        Transgenic mice possessing increased numbers of nociceptors do not exhibit increased behavioral sensitivity in models of inflammatory and neuropathic pain.
        Pain. 2003; 106: 491-500