Down-regulation of μ-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy

Zhang, X; Liu, Bao; Shi, Tie‐Jun Sten; Ju, Gong; Elde, Robert; Hökfelt, Tomas

doi:10.1016/s0306-4522(97)00240-6

Cited by 175 publications

(137 citation statements)

References 88 publications

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“…After sciatic nerve transection (Zhang et al, 1998b) and SNL (Kohno et al, 2005), -receptor mRNA was down-regulated, and the number of -receptor-expressing neurons was decreased in the ipsilateral DRG. Similar effects were observed after PSL (Rashid et al, 2004;Pol et al, 2006), although -receptor immunoreactivity (analyzed by Western blot) was enhanced in another study (Walczak et al, 2005).…”

mentioning

confidence: 97%

“…␦-Receptor mRNA was not altered after PSL or down-regulated after CCI (Obara et al, 2009). All these changes were observed 2 to 28 days after surgeries in lumbar DRG ipsilateral to the nerve injury compared with the contralateral DRG of injured animals (Zhang et al, 1998b;Truong et al, 2003;Pol et al, 2006) or to DRG of naive or sham-operated animals (Zhang et al, 1998b;Sung et al, 2000;Rashid et al, 2004;Kohno et al, 2005;Walczak et al, 2005;Pol et al, 2006;Obara et al, 2009Obara et al, , 2010. ␦-Receptor protein was examined in a CCI-resembling model, in which a loose polyethylene cuff is placed around the sciatic nerve (Mosconi and Kruger model) (Kabli and Cahill, 2007).…”

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confidence: 99%

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Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

2011

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confidence: 97%

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confidence: 99%

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

2011

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“…Similarly, both DOR-and MORimmunoreactive (ir) afferents are mostly distributed in spinal laminae I-II (18,21,32). The presence of DORs on nociceptive afferents is supported by findings that the release of the excitatory neurotransmitters glutamate, substance P (SP), and calcitonin gene-related peptide (CGRP) from afferent C-and Aδ-fibers can be inhibited by activating DORs (33,34).…”

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confidence: 97%

“…In peptidergic small neurons, DOR immunostaining is often associated with large peptide-storing dense-core vesicles (LDCVs), enabling stimulus-induced membrane insertion of DORs (13,15,16,(18)(19)(20). On the other hand, MORs are present on the cell surface of peptidergic small DRG neurons and the local neurons in spinal lamina II (21,22). A few immunohistochemical studies suggest that DORs and MORs are coexpressed in some DRG neurons (23,24).…”

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confidence: 99%

Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

Wang

Zhao²,

Zhong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

189

204

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Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between δ-opioid receptors (DORs) and μ-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca 2+ currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.

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“…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.…”

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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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Down-regulation of μ-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy

Cited by 175 publications

References 88 publications

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

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

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