Chapter 16 Mechanism of Allodynia Evoked by Intrathecal Morphine‐3‐Glucuronide in Mice

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Morphine‐3‐glucuronide (M3G), a main metabolite of morphine, has been proposed as a responsible factor when patients present with the neuroexcitatory side effects (allodynia, hyperalgesia, and myoclonus) observed following systemic administration of large doses of morphine. Indeed, both high‐dose morphine (60 nmol/5 μl) and M3G (3 nmol/5 μl) elicit allodynia when administered intrathecally (i.t.) into mice. The allodynic behaviors are not opioid receptor mediated. This chapter reviews the potential mechanism of spinally mediated allodynia evoked by i.t. injection of M3G in mice. We discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, and dynorphin in the primary afferent fibers following i.t. M3G. It is possible to speculate that i.t. M3G injection could activate indirectly both NK1 receptor and glutamate receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The NO plays an important role in M3G‐induced allodynia. The phosphorylation of extracellular signal‐regulated protein kinase (ERK) in the dorsal spinal cord evoked via NO/cGMP/PKG pathway contributes to i.t. M3G‐induced allodynia. Furthermore, the increased release of NO observed after i.t. injection of M3G activates astrocytes and induces the release of the proinflammatory cytokine, interleukin‐1β. Taken together, these findings suggest that M3G may induce allodynia via activation of NO–ERK pathway, while maintenance of the allodynic response may be triggered by NO‐activated astrocytes in the dorsal spinal cord. The demonstration of the cellular mechanisms of neuronal–glial interaction underlying M3G‐induced allodynia provides a fruitful strategy for improved pain management with high doses of morphine.

Introduction

Morphine is endowed with potent analgesic properties and has been widely used for the management of various kinds of pain, ranging from postoperative pain to chronic pain, including cancer pain. These clinical uses of morphine are often required to provide pain treatment for extended periods. However, the use of opioid analgesics for the treatment of chronic pain states is often offset by the development of tolerance. Thus, high doses of the opioid are required to elicit the same level of pain relief in chronic pain state. However, a large number of clinical studies have reported that high doses of morphine can unexpectedly elicit hyperalgesia (enhanced responses to noxious stimulation), allodynia (pain elicited by normal, innocuous, stimuli), and myoclonus (Ali, 1986, Arner et al., 1988, DeConno et al., 1991, Glavina and Robertshaw, 1988, Krames et al., 1985, Pasternak et al., 1987, Penn and Paice, 1987, Potter et al., 1989, Sjogren et al., 1993, Wert and MacDonald, 1982). Behavioral studies have also demonstrated that morphine at doses far higher than those required for antinociception, injected into the spinal subarachnoid space of rats, produce a spontaneous vocalization/sequeaking and agitation as well as hyperalgesia and allodynia as opposed to antinociception at small doses (Alvarez‐Vega et al., 1998, Tang and Schoenfeld, 1978, Woolf, 1981, Yaksh and Harty, 1988). Furthermore, i.t. administration of high‐dose morphine into mice was found to induce scratching, biting, and licking resembling that of substance P or N‐methyl‐d‐asparatate (NMDA) injected i.t. (Komatsu et al., 2007a, Sakurada et al., 1996a, Sakurada et al., 2002). It has to be noted that spontaneous behavioral activation induced by high‐dose i.t. morphine is irreversible by pretreatment the opioid receptor antagonist naloxone, suggesting a nonopioid mechanism (Sakurada et al., 2001, Watanabe et al., 2003a, Yaksh et al., 1986).

Morphine is known to be metabolized by glucuronidation to two biologically active metabolites, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) (Boerner et al., 1975). M6G has high affinity for the μ‐opioid receptor (Lonze and Ginty, 2002, Parkinson et al., 1990, Paul et al., 1989) and appears to be a more potent opioid agonist than morphine (Frances et al., 1992, Osborne et al., 2000, Parkinson et al., 1990, Paul et al., 1989). In contrast, M3G does not bind to μ‐, δ‐, or κ‐opioid receptors (Lonze and Ginty, 2002, Parkinson et al., 1990) and appears to be devoid of analgesic activity (Parkinson et al., 1990, Yaksh et al., 1986). M3G also does not interact with NMDA, GABAA, or glycine receptors (Bartlett et al., 1994). However, in spite of these apparent lacks of activity, i.t. and intracerebroventricular (i.c.v.) administrations of M3G have been reported to evoke a range of excitatory behaviors including hyperalgesia, allodynia, myoclonus, and seizures in rats (Smith, 2000). These findings are consistent with previous data that one of the main morphine metabolites, for example M3G, may be responsible for the development of hyperalgesia, allodynia, and myoclonus during clinical morphine therapy (DeConno et al., 1991, Sjogren et al., 1993). Therefore, exploring possible mechanisms of M3G‐induced nociception may be clinically useful to improve pain management with morphine and opioid analgesics.

Section snippets

Mechanism of M3G‐Induced Allodynia: Spinal Release of Substance P and Glutamate

Much attention has to be paid that some effects of synthetic or endogenous compounds may be attributed to the action of their metabolites rather than the parent compound. M3G concentrations in the cerebrospinal fluid may account for more than half of morphine administered systemically to rats and humans (Smith, 2000). Additionally, human brain homogenates have been shown to metabolize morphine at nanomolar concentrations to M3G and M6G (Yamada et al., 2003), suggesting the idea that M3G in the

Mechanism of M3G‐Induced Allodynia: Spinal Activation of NO/cGMP/PKG Pathway

Substance P and glutamate released from presynaptic sites in response to i.t. M3G could activate NK1 and NMDA receptors, which could trigger a feed forward mechanism of stimulation of neuronal nitric oxide synthase (nNOS) activity via mechanism largely dependent on Ca2+. Increases in intracellular Ca2+ either by extracellular Ca2+ influx through NMDA receptor or Ca2+ channels as well as release from intracellular Ca2+ stores via production of inositol‐1,4,5‐triphosphate after activation of

Mechanism of M3G‐Induced Allodynia: Spinal ERK Activation

The mitogen‐activated protein kinase (MAPK) is a family of evolutionary conserved molecules that plays a critical role in intracellular signal transduction and consists of ERK (extracellular signal‐regulated protein kinase; p44/42 MAPK), p38, and JNK (c‐Jun N‐terminal kinase). Although ERK was originally implicated only in regulating the mitosis, proliferation, differentiation, and survival of cells during development, they are now widely recognized also to play an important role in neuronal

Mechanism of M3G‐Induced Allodynia; Spinal Astrocyte Activation

Glial cells play an important role in the control of pain; in fact, it is known that neuronal plasticity is triggered by many inflammatory mediators and these are mainly produced by glial cells in the central nervous system. Indeed, in the past several years, more and more attention has been paid to neuron–glia interaction as a driving force for the development and maintenance of abnormal pain (Ji and Strichartz, 2004, Marchand et al., 2005, Scholz and Woolf, 2007, Tsuda et al., 2005, Watkins

References (102)

  • A. Holguin et al.

    HIV‐1 gp120 stimulates proinflammatory cytokine‐mediated pain facilitation via activation of nitric oxide synthase‐I (nNOS)

    Pain

    (2004)
  • P. Honore et al.

    Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons

    Neuroscience

    (2000)
  • S. Impey et al.

    Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB‐dependent transcription and ERK nuclear translocation

    Neuron

    (1998)
  • S. Impey et al.

    Making new concentration: Role of ERK/MAP kinase signaling in neuronal plasticity

    Neuron

    (1999)
  • R.R. Ji et al.

    Neuronal plasticity and signal transduction in nociceptive neurons: Implications for the initiation and maintenance of pathological pain

    Neurobiol. Dis.

    (2001)
  • R.R. Ji et al.

    Central sensitization and longterm potentiation—Do pain and memory share similar mechanism?

    Trends Neurosci.

    (2003)
  • T. Komatsu et al.

    Extracellular signal‐regulated kinase (ERK) and nitric oxide synthase mediate intrathecal morphine‐induced nociceptive behavior

    Neuropharmacology

    (2007)
  • T.M. Laughlin et al.

    Spinally administered dynorphin A produces long‐lasting allodynia: Involvement of NMDA but not opioid receptors

    Pain

    (1997)
  • I.J. Lever et al.

    The signaling components of sensory fiber transmission involved in the activation of ERK MAP kinase in the mouse dorsal horn

    Mol. Cell. Neurosci.

    (2003)
  • B.E. Lonze et al.

    Function and regulation of CREB family transcription factors in the nervous system

    Neuron

    (2002)
  • T.P. Malan et al.

    Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve‐injured rats

    Pain

    (2000)
  • S.T. Meller et al.

    Nitric oxide (NO) and nociceptive processing in the spinal cord

    Pain

    (1993)
  • S.T. Meller et al.

    The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat

    Neuropharmacology

    (1994)
  • K. Morita et al.

    Glycinergic mediation of tactile allodynia induced by platelet‐activating factor (PAF) through glutamate‐NO‐cyclic GMP signalling in spinal cord in mice

    Pain

    (2008)
  • A. Morozov et al.

    Rap1 couples camp signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory

    Neuron

    (2003)
  • K. Obrietan et al.

    Circadian regulation of cAMP response element‐mediated gene expression in the suparachiasmatic nuclei

    J. Biol. Chem.

    (1999)
  • G.W. Pasternak et al.

    Morphine‐6‐glucuronide, a potent mu agonist

    Life Sci.

    (1987)
  • T. Sakurada et al.

    Spinally‐mediated behavioral responses evoked by intrathecal high‐dose morphine: Possible involvement of substance P in the mouse spinal cord

    Brain Res.

    (1996)
  • T. Sakurada et al.

    Involvement of nitric oxide in spinally mediated capsaicin‐ and glutamate‐induced behavioural responses in the mouse

    Neurchem. Int.

    (1996)
  • C. Sakurada et al.

    Antinociceptive effect of spinally injected L‐NAME on the acute nociceptive response induced by low concentrations of formalin

    Neurochem. Int.

    (2001)
  • T. Sakurada et al.

    Intrathecal high‐dose morphine induces spinally‐mediated behavioral responses through NMDA receptors

    Mol. Brain Res.

    (2002)
  • A. Schmidtko et al.

    Inhibition of cyclic guanosine 5′‐monophosphate‐dependent protein kinase I (PKG‐I) in lumbar spinal cord reduces formalin‐induced hyperalgesia and PKG upregulation

    Nitric Oxide

    (2003)
  • J.B. Siegan et al.

    Alterations in rat spinal cord cGMP by peripheral nerve injury and adrenal medullary transplantation

    Neurosci. Lett.

    (1996)
  • P. Sjogren et al.

    Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine

    Pain

    (1993)
  • S.R. Skilling et al.

    Selective potentiation of NMDA‐induced activity and release of excitatory amino acids by dynorphine: Possible roles in paralysis and neurotoxicity

    Brain Res.

    (1992)
  • C.S. Sung et al.

    Intrathecal interleukin‐1beta administration induces themal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord

    Brain Res.

    (2004)
  • S. Sweitzer et al.

    Intrathecal interleukin‐1 receptor antagonist in combunation with soluble tumor necrosis factor receptor exhibits an anti‐allodynic action in a rat model of neuropathic pain

    Neuroscience

    (2001)
  • Y.H. Tai et al.

    Amitriptyline suppresses neuroinflammation and up regulates glutamate transporters in morphine‐tolerant rats

    Pain

    (2006)
  • A.H. Tang et al.

    Comparison of subcutaneous and spinal subarachnoid injections of morphine and naloxone in analgesic tests in rat

    Eur. J. Pharmacol.

    (1978)
  • I. Tegeder et al.

    Dual effects of spinally delivered 8‐bromo‐cyclic guanosine mono‐phosphate (8‐bromo‐cGMP) in formalin‐induced nociception in rats

    Neurosci. Lett.

    (2002)
  • M. Tsuda et al.

    Neuropathic pain and spinal microglia: A big problem from molecules in “small” glia

    Trends Neurosci.

    (2005)
  • R. Wagner et al.

    Pre‐emptive dynorphine and N‐methyl‐d‐asparatate glutamate receptor antagonism alters spinal immunocytochemistry but not allodynia following complete peripheral nerve injury

    Neurocsience

    (1996)
  • C. Watanabe et al.

    The role of spinal nitric oxide and glutamate in nociceptive behaviour evoked by high‐dose intrathecal morphine in rats

    Pain

    (2003)
  • C. Watanabe et al.

    Evidence that nitric oxide‐glutamate cascade modulates spinal antinociceptive effect of morphine: A behavioural and microdialysis study in rats

    Brain Res.

    (2003)
  • L.R. Watkins et al.

    Glial activation: A driving force for pathological pain

    Trends Neurosci.

    (2001)
  • N. Yonehara et al.

    Involvement of NMDA‐nitric oxide pathways in the development of tactile hypersensitivity evoked by the loose‐ligation of inferior alveolar nerves in rats

    Brain Res.

    (2003)
  • N.M.K. Ali

    Hyperalgesic response in a patient receiving high concentrations of spinal morphine

    Anesthesiology

    (1986)
  • M. Alvarez‐Vega et al.

    Comparison of the effects of calmidazolium, morphine and bupivacaine on N‐methyl‐d‐aspartate‐ and septide‐induced nociceptive behaviour

    Naunyn‐Schmiedeberg's Arch. Pharmacol.

    (1998)
  • S. Arner et al.

    Clinical experience of long‐term treatment with epidural opioids—A nationwide survey

    Acta Anaesthesiol. Scand.

    (1988)
  • S.E. Bartlett et al.

    Pharmacology of morphine and morphine‐3‐glucronide at opioid, excitatory amino acis, GABA and glycine binding site

    Pharmacol. Toxicol.

    (1994)
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