The loss of antinociceptive efficacy of spinal morphine in rats with nerve ligation injury is prevented by reducing spinal afferent drive

Ossipov, Michael H.; Lopez, Y.; Nichols, Michael L.; Bian, Di; Porreca, Frank

doi:10.1016/0304-3940(95)12022-v

Cited by 135 publications

(73 citation statements)

References 23 publications

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“…This result ®ts in well with results from previous studies in di erent models of neuropathic pain using either systemic (Advokat & Rhein, 1993;Kauppila et al, 1998) or intrathecal (Yamamoto & Yaksh, 1992;Ossipov et al, 1995;Nichols et al, 1997) routes of administration. In these studies, however, the NMDA receptor antagonist failed to modulate the e ect of morphine in the contralateral paw (Yamamoto & Yaksh, 1992) or in sham-operated rats (Ossipov et al, 1995). This contrasts with our results, in which the e ect of the combination of (+)-HA966 and morphine remained signi®cant and dose-dependent in the contralateral hindpaw as well as in uninjured rats with the relative potency being nerve-injured hindpaw4contralateral hindpaw4uninjured rat.…”

Section: Discussionsupporting

confidence: 90%

“…It has been shown that NMDA receptor antagonism reverses the ine ectiveness of morphine in depressing dorsal horn neuronal activity (Chapman & Dickenson, 1992). In addition, the sensitivity of thermal hyperalgesia (Yamamoto & Yaksh, 1992;Ossipov et al, 1995) and mechanical allodynia (Nichols et al, 1997) to intrathecal morphine can be restored by concomitant intrathecal administration of a NMDA receptor antagonist in di erent models of neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

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The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

Christensen

Idänpään-Heikkilä

Guilbaud

et al. 1998

British J Pharmacology

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1 We evaluated the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966), to modulate the antinociceptive action of systemic morphine in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) and thermal (struggle latency to hindpaw immersion into a water bath) stimuli were used. 2 In the mechanical test, morphine (0.05, 0.1 and 0.3 mg kg 71 , i.v.) alone produced dose-dependent e ects in both neuropathic and uninjured rats. Likewise, morphine (0.1, 0.3 and 1 mg kg 71 , i.v.) dosedependently increased struggle latencies of the nerve-injured hindpaw in the hot noxious (468C) test but was ine ective in the non-noxious warm (448C) and cold (108C) test. 3 Pretreatment with (+)-HA966 (2.5 mg kg 71 , s.c.) dose-dependently enhanced the e ect of morphine in the mechanical test with the relative potency being nerve-injured hindpaw4contralateral hindpaw4uninjured rat. 4 Likewise, (+)-HA966 dose-dependently enhanced the e ect of morphine against a hot (468C) stimulus and produced, in combination with morphine, a dose-dependent e ect against a warm (448C) stimulus. In the cold (108C) test, (+)-HA966 reversed the ine ectiveness of the highest dose of morphine. 5 Naloxone blocked the e ect of the combination of (+)-HA966 with morphine in all tests. The drug combination produced no motor de®cits in animals using the rotarod test. 6 These ®ndings suggest that combined administration of antagonists, acting at the glycine site of the NMDA receptor complex and morphine may be a promising approach in the treatment of neuropathic and acute pain.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

Christensen

Idänpään-Heikkilä

Guilbaud

et al. 1998

British J Pharmacology

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“…That is, even when the GT expression was reduced after the initial stage of CCI, an enhanced GT uptake activity by riluzole, as demonstrated in our in vitro glutamate uptake assay, was able to offset significantly the effects of GT downregulation on neuropathic pain behaviors in CCI rats. Similar effects of regulating GT uptake activity have been observed on the development of morphine tolerance (Nakagawa et al, 2001;Mao et al, 2002a,b), a process that has been shown to share certain common glutamatemediated cellular and intracellular mechanisms (Mao et al, 1994(Mao et al, , 1995Ossipov et al, 1995).…”

Section: Possible Mechanisms Of Gt Changes After CCImentioning

confidence: 57%

Altered Expression and Uptake Activity of Spinal Glutamate Transporters after Nerve Injury Contribute to the Pathogenesis of Neuropathic Pain in Rats

2003

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The central glutamatergic system has been implicated in the pathogenesis of neuropathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after chronic constriction nerve injury (CCI) and contributed to neuropathic pain behaviors in rats. CCI induced an initial GT upregulation up to at least postoperative day 5 primarily within the ipsilateral spinal cord dorsal horn, which was followed by a GT downregulation when examined on postoperative days 7 and 14 by Western blot and immunohistochemistry. Intrathecal administration of the tyrosine kinase receptor inhibitor K252a and the mitogen-activated protein kinase inhibitor PD98059 for postoperative days 1-4 reduced and nearly abolished the initial GT upregulation in CCI rats, respectively. Prevention of the CCI-induced GT upregulation by PD98059 resulted in exacerbated thermal hyperalgesia and mechanical allodynia reversible by the noncompetitive NMDA receptor antagonist MK-801, indicating that the initial GT upregulation hampered the development of neuropathic pain behaviors. Moreover, CCI significantly reduced glutamate uptake activity of spinal GTs when examined on postoperative day 5, which was prevented by riluzole (a positive GT activity regulator) given intrathecally twice a day for postoperative days 1-4. Consistently, riluzole attenuated and gradually reversed neuropathic pain behaviors when the 4 d riluzole treatment was given for postoperative days 1-4 and 5-8, respectively. These results indicate that changes in the expression and glutamate uptake activity of spinal GTs may play a critical role in both the induction and maintenance of neuropathic pain after nerve injury via the regulation of regional glutamate homeostasis, a new mechanism relevant to the pathogenesis of neuropathic pain.

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“…In patients with neuropathic pain, however, the analgesic potency of MOR agonists is reduced (3,4). The opioid effects are also diminished in animal models of neuropathic pain (5)(6)(7). MORs expressed at primary sensory neurons and their central terminals in the spinal dorsal horn are essential for the analgesic effects of opioids (8 -10).…”

mentioning

confidence: 99%

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

Zhang¹,

Chen²,

Laumet

et al. 2016

Journal of Biological Chemistry

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The -opioid receptor (MOR, encoded by Oprm1) agonists are the mainstay analgesics for treating moderate to severe pain. Nerve injury causes down-regulation of MORs in the dorsal root ganglion (DRG) and diminishes the opioid effect on neuropathic pain. However, the epigenetic mechanisms underlying the diminished MOR expression caused by nerve injury are not clear. G9a (encoded by Ehmt2), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined the role of G9a in diminished MOR expression and opioid analgesic effects in animal models of neuropathic pain. We found that nerve injury in rats induced a long-lasting reduction in the expression level of MORs in the DRG but not in the spinal cord. Nerve injury consistently increased the enrichment of the G9a product histone 3 at lysine 9 dimethylation in the promoter of Oprm1 in the DRG. G9a inhibition or siRNA knockdown fully reversed MOR expression in the injured DRG and potentiated the morphine effect on pain hypersensitivity induced by nerve injury. In mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce the expression level of MORs and the morphine effect. In addition, G9a inhibition or Ehmt2 knockout in DRG neurons normalized nerve injury-induced reduction in the inhibitory effect of the opioid on synaptic glutamate release from primary afferent nerves. Our findings indicate that G9a contributes critically to transcriptional repression of MORs in primary sensory neurons in neuropathic pain. G9a inhibitors may be used to enhance the opioid analgesic effect in the treatment of chronic neuropathic pain.Chronic neuropathic pain resulting from damage to the peripheral or central nervous system causes agonizing suffering and reduced quality of life. Neuropathic pain is often resistant to conventional analgesic treatments and remains a major therapeutic challenge. Opioid drugs such as morphine produce their therapeutic effects through binding to the -opioid receptors (MORs, 3 encoded by Oprm1) (1, 2) and are widely used to treat moderate to severe pain. In patients with neuropathic pain, however, the analgesic potency of MOR agonists is reduced (3, 4). The opioid effects are also diminished in animal models of neuropathic pain (5-7). MORs expressed at primary sensory neurons and their central terminals in the spinal dorsal horn are essential for the analgesic effects of opioids (8 -10). Peripheral nerve injury reduces the expression level of MORs in the dorsal root ganglion (DRG), contributing to the loss of opioid analgesic efficacy in neuropathic pain (6,11,12). However, the epigenetic mechanisms by which nerve injury leads to diminished MOR expression in the DRG remain unclear.Transcriptional homeostasis is largely maintained by the dynamic balance between positive and negative regulation of gene transcription. Gene expression is critically controlled by chromatin structure and the modification status of histone tails (13-15). DNA methylation and histone modifications are two major ...

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The loss of antinociceptive efficacy of spinal morphine in rats with nerve ligation injury is prevented by reducing spinal afferent drive

Cited by 135 publications

References 23 publications

The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

Altered Expression and Uptake Activity of Spinal Glutamate Transporters after Nerve Injury Contribute to the Pathogenesis of Neuropathic Pain in Rats

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

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