Chapter 16 Mechanism of Allodynia Evoked by Intrathecal Morphine‐3‐Glucuronide in Mice
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)
- et al.
Triplicate synapses: Glia, the unacknowledged partner
Trends Neurosci.
(1999) - et al.
Dynorphine A increases substance P release from trigeminal primary afferent C‐fibers
Eur. J. Pharmacol.
(1999) - et al.
Loss of anti nociceptive spinal/supraspinal morphine synergy in nerve‐injured rats; restoration by MK‐801 or dynorphine antiserum
Brain Res.
(1999) - et al.
Activation of the ERK signaling pathway contributes naloxone‐precipitated withdrawal in morphine‐dependent rats
Pain
(2005) - et al.
Cross talk between nitric oxide and ERK1/2 signaling pathway in the spinal cord mediates naloxone‐precipitated withdrawal in morphine‐dependent rats
Neuropharmacology
(2006) - et al.
Dissociation of microglial activation and neuropathic behaviors following peripheral nerve injury in the rat
J. Neuroimmunol
(1997) - et al.
Activation of p38 mitogen‐activated protein kinase in spinal microglia mediated morphine antinociceptive tolerance
Brain Res.
(2006) - et al.
Hyperalgesia and myoclonus with intrathecal infusion of high‐dose morphine
Pain
(1991) - et al.
Micloglial reactions after subcutaneous formalin injection into the rat hind paw
Neuroscience
(1999) - et al.
Carrageenan induced inflammation alters the content of i‐cGMP and i‐cAMP in the dorsal horn of the spinal cord
Brain Res.
(1994)