Intrathecal Injection of Metabotropic Glutamate Receptor Subtype 3 and 5 Agonist/Antagonist Attenuates Bone Cancer Pain by Inhibition of Spinal Astrocyte Activation in a Mouse Model

Ren, Bo; Gu, Xiaoping; Zheng, Yaguo; Liu, Chenglong; Wang, Dan; Sun, Yue; Ma, Zhengliang

doi:10.1097/aln.0b013e31823de68d

Cited by 70 publications

(48 citation statements)

References 47 publications

(43 reference statements)

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“…However, our studies did not detect similar tonically active inhibitory mechanisms in the control of nociceptive bladder reflexes. Bladder overactivity was not altered after administration of LY341495, which induces hyperalgesia and enhances nociceptive behavior in somatic pain models (9,34). However, the drug did suppress TNS-induced inhibition of bladder overactivity.…”

Section: Discussionmentioning

confidence: 91%

“…Because naloxone and LY341495 were both administered systemically, it is impossible to determine their site of action. However, it is likely that these drugs interact at least in part at synapses in the lumbosacral spinal cord on the basis of the following observations: 1) group II mGluR and opioid receptors are expressed in the spinal dorsal horn (6,8,21,22,32,41); 2) intrathecal administration of group II mGluR agonists suppress nociceptive behavior (13,23,24,34); 3) AAinduced bladder overactivity is mediated by a reflex pathway organized in the spinal cord (17); 4) our previous study (39) suggested that TNS inhibition of AA-induced bladder overactivity could be mediated by suppression of transmission at a spinal interneuronal synapse prior to the sacral parasympathetic preganglionic neurons; and 5) spinal opioid receptors have a prominent inhibitory effect on micturition (12,20,42,43). Figure 6 shows a hypothetical spinal mechanism for TNS inhibition, which is intended to facilitate the discussion about possible sites of interaction between naloxone and LY341495.…”

Section: Discussionmentioning

confidence: 99%

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Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Matsuta

Mally

Zhang

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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(mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under ␣-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly (P Ͻ 0.0001) reduced bladder capacity to 26.6 Ϯ 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 Ϯ 8.3% at 2T (P Ͻ 0.01) and 80.8 Ϯ 9.2% at 4T (P ϭ 0.0001) of saline control capacity. LY341495 (0.1-5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders.neurotransmitter; neuromodulation; bladder; cat GLUTAMATERGIC NEUROTRANSMISSION involves activation of both ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluR) that consist of eight subtypes classified into group I (mGluR 1 and 5), group II (mGluR 2 and 3), and group III (mGluR 4,6,7,and 8). An interaction between iGluR and opioid receptor mechanisms is believed to be important in pain pathways, because block of ionotropic Nmethyl-D-aspartate (NMDA) receptors enhances the antinociceptive effect of morphine (an opioid receptor agonist) (14,28,36,37). Recently, the interaction between mGluR and opioid receptors has also been identified in studies of opioid-induced antinociception (15,16,29,45). Opioid-induced antinociceptive effects were enhanced by antagonists (15,16,45) and agonists (29) of group II mGluR in different types of somatic nociception. Currently, it is unknown whether this interaction between group II mGluR and opioid receptors occurs in visceral nociceptive mechanisms.Recent results from this laboratory (38) revealed that tibial nerve stimulation (TNS) inhibits bladder overactivity elicited by intravesical infusion of acetic acid (AA), which stimulates nociceptive bladder afferent nerves. This TNS-induced antinociceptive effect is completely eliminated by naloxone (an opioid...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Matsuta

Mally

Zhang

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Thus, targeting such a heteromer with bivalent ligands that activate MOR with concomitant antagonism of mGluR 5 , could represent a promising strategy to develop analgesics with enhanced potency and reduced adverse effects on spinal administration. Such ligands should be particularly effective in the treatment of inflammatory pain arising from spinal cord injury (15), transient nerve root compression (16), and other conditions in which glutamate is up-regulated in neurons and glia. In this regard, as intrathecal administration of mGluR 5 antagonist is known to inhibit activation of spinal astrocytes in a mouse model and in vitro, targeting a MOR-mGluR 5 heteromer may be a useful strategy in the pharmacotherapy of inflammatory pain (17).…”

Section: Discussionmentioning

confidence: 99%

Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception

Akgün

Javed

Lunzer

et al. 2013

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

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The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR 5 ) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR 5 in glia and neurons, together with reports that suggest coexpressed MOR/mGluR 5 receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR 5 antagonist pharmacophores linked through spacers of varying length (10-24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED 50 ∼9 fmol per mouse), whereas in untreated mice its ED 50 was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED 50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR 5 heteromer. The finding that MMG22 possesses a >10 6 therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.MPEP | tolerance | respiratory depression T he excitatory neurotransmitter, glutamate, in the central nervous system (CNS) is an important mediator of opioid nociception, dependence, and withdrawal (1). Glutamate exerts its effect via two different classes of glutamate receptors: ionotropic and metabotropic. Among the metabotropic receptors (mGluRs), the receptor-5 subtype (mGluR 5 ) is widely distributed in the CNS (2), where it modulates synaptic transmission, neuronal excitability, and plasticity. The mGluR 5 is a class C G protein-coupled receptor (GPCR), the activation of which is mediated by binding of glutamate to its extracellular Venus flytrap domain. It is noteworthy that the selective mGluR 5 antagonist, 2-methyl-6-(phenylethynyl) pyridine (MPEP), acts allosterically by binding to the seven transmembrane (7TM) domain of the receptor (3).Reports of presence of the mu opioid receptor (MOR) and mGluR 5 in the spinal cord and the ability of coadministered MPEP and morphine to enhance morphine antinociception and suppress morphine-induced tolerance and dependence suggest a design strategy for the development of potent analgesics based on the targeting of both MOR and mGluR 5 (4-6). Given evidence (7) that supports the physical association of coexpressed MOR and mGluR 5 as heteromer (MOR-mGluR 5 ) in cultured cells, and the presence of MOR and mGluR 5 in t...

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“…Patients with cancer pain were evaluated for mechanical allodynia [52] Paw withdrawal responses to von Frey monoilaments in bone cancer mice or rats [1,[53][54][55] Heat hyperalgesia Patients with cancer pain were evaluated for heat hyperalgesia [52] Paw withdrawal latency and frequency in response to static heat stimuli in mice or rats [53,54,56] Movement-evoked pain The use of a pain verbal rating scale during movement [57] Count the number of spontaneous linches of the hind limb in bone tumor mice [55] Note: most human cancer pain studies have employed visual analogue scales (VAS), numerical rating scales, or verbal reporting to quantify pain, and thus it is often diicult to compare nociceptive behavioral testing results from cancer pain studies using animal models with human cancer pain studies because of the diferences in pain assessment. …”

Section: Mechanical Allodyniamentioning

confidence: 99%

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

Smeester¹,

Moriarity²,

Beitz³

2017

Osteosarcoma - Biology, Behavior and Mechanisms

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Osteosarcoma is the most common primary cancer of the bone and third most common cancer in children and adolescents with approximately 900 new cases annually in the United States. A major facet of osteosarcoma is its high level of genomic instability, in particular chromosomal instability, which is the result of increased or decreased chromosome number in a cell. Furthermore, pain is the most common symptomatic feature of osteosarcoma that lacks efective therapy. Pain in osteosarcoma is relatively more complicated than many other painful conditions requiring a more thorough understanding of its etiology, pathobiology, and neurobiology to allow the development of beter therapies for reducing pain in osteosarcoma patients. Studies are underway to deine the diverse modalities of presentation, growth, development, metastases, and nociception in osteosarcoma. New data from human studies in combination with data from studies incorporating transgenic mouse models of osteosarcoma are providing valuable insights into the mechanisms underlying the development of both the tumor and the tumor-induced pain. These new data will undoubtedly lead to improved prognoses, as well as the development of novel therapeutics that will signiicantly decrease bone cancer pain.

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Intrathecal Injection of Metabotropic Glutamate Receptor Subtype 3 and 5 Agonist/Antagonist Attenuates Bone Cancer Pain by Inhibition of Spinal Astrocyte Activation in a Mouse Model

Abstract: Spinal mGluR3 activation or mGluR5 inhibition reduced bone cancer pain. Inhibition of spinal astrocyte activation may contribute to the analgesic effects. These findings may lead to novel strategies for the treatment of bone cancer pain.

Cited by 70 publications

References 47 publications

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

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