Contribution of Chemokine CCL2/CCR2 Signaling in the Dorsal Root Ganglion and Spinal Cord to the Maintenance of Neuropathic Pain in a Rat Model of Lumbar Disc Herniation

Zhu, Xiaohui; Cao, Sheng‐Li; Zhu, Ming-Di; Liu, Jinqian; Chen, Junjie; Gao, Yong‐Jing

doi:10.1016/j.jpain.2014.01.492

Cited by 74 publications

(72 citation statements)

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“…These results complemented our previous findings describing the analgesic effects of RS504393 and its beneficial influence on CCI-elevated spinal upregulation of CCR2 and CCL2 under neuropathy (Piotrowska et al 2016a). Our results are in agreement with others, showing that single intracisternal injections of CCR2 antagonist reduced neuropathic pain induced by inferior alveolar nerve transection (Zhang et al 2012) and lumbar disc herniation (Zhu et al 2014). Importantly, our study is, to our knowledge, the first to identify that chronic administration of RS504393 significantly enhanced opioid effectiveness in a rat neuropathic pain model.…”

Section: Discussionsupporting

confidence: 94%

“…Several studies have suggested that endogenous CCL2 is one of the key mediators of spinal glia activation after nerve injury (Thacker et al 2009; Gao and Ji 2010; Parpura and Zorec 2010; Zhao et al 2012; Zhu et al 2014). Baamonde et al (2011) showed that intrathecal administration of CCL2 provokes glial activation and the release of pronociceptive molecules, such as IL-1beta, that together with CCL2, leads to the sensitization of NMDA and AMPA receptors and contributes to the development of thermal hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…The control group received vehicle ( V ; 12% DMSO) at the same schedule. The concentration of examined substances were selected according to the literature (Zhu et al 2014; Piotrowska et al 2016a) and our preliminary study. The dosing schedule (Scheme 1) was selected basing on our previous research, which demonstrated that substances which may modulate microglial cells need to be administered preemptively (Rojewska et al 2015; Kwiatkowski et al 2016; Jurga et al 2016) as the activated microglia is very difficult to fade out afterwards.…”

Section: Methodsmentioning

confidence: 99%

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The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

Kwiatkowski

Piotrowska

Rojewska

et al. 2017

J Neuroimmune Pharmacol

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Increasing evidence has indicated that activated glial cells releasing nociceptive factors, such as interleukins and chemokines, are of key importance for neuropathic pain. Significant changes in the production of nociceptive factors are associated with the low effectiveness of opioids in neuropathic pain. Recently, it has been suggested that CCL2/CCR2 signaling is important for nociception. Here, we studied the time course changes in the mRNA/protein level of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we examined the influence of intrathecal preemptive and repeated (daily for 7 days) administration of RS504393, CCR2 antagonist, on pain-related behavior and the associated biochemical changes of some nociceptive factors as well as its influence on opioid effectiveness. We observed simultaneous upregulation of Iba-1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we demonstrated that repeated administration of RS504393 not only attenuated tactile/thermal hypersensitivity but also enhanced the analgesic properties of morphine and buprenorphine under neuropathy. Our results proof that repeated administration of RS504393 reduced the mRNA and/or protein levels of pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide synthase (iNOS), and some of their receptors in the spinal cord and/or DRG. Furthermore, RS504393 elevated the spinal protein level of antinociceptive IL-1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a promising target for diminishing neuropathic pain and enhancing the opioid analgesic effects.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

Kwiatkowski

Piotrowska

Rojewska

et al. 2017

J Neuroimmune Pharmacol

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“…While there is no consensus regarding the subpopulation of nociceptors expressing CCR2 [13; 66], it is not expressed by dorsal horn neurons [66]. While, some studies have failed to detect the expression of CCR2 [14; 37; 38; 50], others have provided evidence by means of Western blot [61; 65] and immunofluorescence [8; 13; 66; 68] that CCR2 is constitutively expressed in DRG neurons of naïve rats. Furthermore, in vitro electrophysiological studies performed in DRG neurons obtained from control rats have shown that MCP-1, but not vehicle, activates between 6 to 10% of those neurons [57; 62].…”

Section: Discussionmentioning

confidence: 99%

Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat

Álvarez

Green

Levine

2014

Pain

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Summary Whether MCP-1 contributes to chronic musculoskeletal pain is unknown. We provide evidence that MCP-1 induces acute muscle hyperalgesia and a state of chronic nociceptive sensitization. While raised levels of monocyte chemoattractant protein 1 (MCP-1) have been observed in patients with chronic muscle pain, direct evidence for its role as an algogen in skeletal muscle is still lacking. In the rat, MCP-1 induces a dose-dependent mechanical hyperalgesia lasting for up to 6 weeks. Following recovery, rats exhibited a markedly prolonged hyperalgesia to an intramuscular injection of prostaglandin E2, hyperalgesic priming. Intrathecal pre-treatment with isolectin B4 (IB4)-saporin, which selectively destroys IB4-positive (IB4+) nociceptors, markedly decreased MCP-1 induced hyperalgesia and prevented the subsequent development of priming. To evaluate the involvement of MCP-1 in stress-induced chronic pain we administered, intrathecally (i.t.), antisense (AS) or mismatch (MM) oligodeoxynucleotides directed against CCR2 (the canonical receptor for MCP-1) mRNA, during the exposure to water avoidance stress, a model of stress-induced persistent muscle pain. The AS treatment attenuated this hyperalgesia, whereas IB4-saporin abolished water avoidance stress-induced muscle hyperalgesia and prevented stress-induced hyperalgesic priming. These results indicate that MCP-1 induces persistent muscle hyperalgesia and a state of latent chronic sensitization to other algogens, by action on its cognate receptor on IB4+ nociceptors. Since MCP-1 also contributes to stress-induced widespread chronic muscle pain, it should be considered as a player in chronic musculoskeletal pain syndromes.

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“…Interestingly, spinal microglia activation occurs during the early phase of neuropathic pain, suggesting that microglia may be important for initiation of neuropathic pain, while astrocytes are important for its maintenance. In addition, one study has demonstrated that CCL2/CCR2 signaling in the DRG and spinal cord is involved in neuropathic pain via distinct mechanisms [102]. Nucleus pulposus-induced mechanical allodynia is attenuated by treatment with the CCR2 antagonist RS504393 in radicular neuropathic pain.…”

Section: Mechanism Of Neuropathic Painmentioning

confidence: 99%

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

Lim

Kim

2016

BioMed Research International

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Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment.

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Contribution of Chemokine CCL2/CCR2 Signaling in the Dorsal Root Ganglion and Spinal Cord to the Maintenance of Neuropathic Pain in a Rat Model of Lumbar Disc Herniation

Cited by 74 publications

References 50 publications

The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

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