Direct and indirect pharmacological modulation of CCL2/CCR2 pathway results in attenuation of neuropathic pain — In vivo and in vitro evidence

Piotrowska, Anna; Kwiatkowski, Klaudia; Rojewska, Ewelina; Ślusarczyk, Joanna; Makuch, Wioletta; Basta‐Kaim, Agnieszka; Przewłocka, Barbara; Mika, Joanna

doi:10.1016/j.jneuroim.2016.04.017

Cited by 52 publications

(84 citation statements)

References 82 publications

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“…CCL2, CCL3, CCL5, IL-1β, and IL-6 are upregulated in damaged nerves, DRGs, and spinal cord dorsal horn (60–63) in variety of models and neuropathic pain is decreased by antagonists, neutralizing antibodies, microglia inhibitors, or in CCL2 deficient mice (62, 64–66). However, in the present study, CCL3 expression was elevated at all ages at PS1 in the root compression and at PS7 in the nerve compression injury, which is not consistent with the appearance of thermal or mechanical hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat

et al. 2016

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Neuropathic pain is chronic pain that develops after nerve injury and is less frequent in infants and children than in adults. Likewise, in animal models of neuropathic pain, allodynia and hyperalgesia are non-existent or attenuated in the infant, with a “switch” during development by which acute nerve injury transitions to chronic pain. Concomitant with the delay in neuropathic pain, there is a parallel delay in the ability of nerve injury to activate the immune system. Models of neuropathic pain in the infant have used various ligation methods and find that neuropathic pain does not occur under after postnatal days 21–28 (PN21–PN28), linked to activation of immune processes and developmental regulation of anti-inflammatory cytokines. We applied a model of neuropathic pain in the adult using a transient compression of the cervical nerve or nerve root in infant rats (injured at 10, 14, 21, or 28 days of age) to define transition periods during which injury results in no change in thermal and mechanical pain sensitivity or in short-term changes in pain. There was little to no hyperalgesia when the injury was imposed at PN10, but significant thermal hyperalgesia and mechanical allodynia 1 day after compression injury when performed at PN14, 21, or 28. Thermal withdrawal latencies returned to near baseline by 7 days postsurgery when the injuries were at PN14, and lasted up to 14 days when the injury was imposed at PN28. There was mechanical allodynia following injury at 1 day postinjury and at 14 days after injury at PN14. Measurements of mRNA from spinal cord at 1, 7, and 14 days postinjury at PN14, 21, and 28 showed that both the magnitude and duration of elevated immune markers and chemokines/cytokines were greater in the older animals, corresponding to the development of hyperalgesia. Thus, we confirm the late onset of neuropathic pain but found no evidence of emergent hyperalgesia if the injury was before PN21. This may be due to the use of a transient, and not sustained, compression ligation model.

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Section: Discussionmentioning

confidence: 99%

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat

et al. 2016

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“…injections were implanted according to the method described by Yaksh and Rudy (1976) and our earlier publications (Popiolek-Barczyk et al 2015; Rojewska et al 2015; Piotrowska et al 2016a). Just before operation each rat was anesthetized with sodium pentobarbital (60 mg/kg) administered intraperitoneally ( i.p.)…”

Section: Methodsmentioning

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%

“…It has already been shown that C-C motif chemokine ligand 2 (CCL2; Monocyte Chemoattractant Protein-1 ; MCP-1) and its receptor C-C chemokine receptor type 2 (CCR2) play crucial roles in neuropathic pain development (Gao and Ji 2010; Van Steenwinckel et al 2011; Zhang et al 2012). Piotrowska et al (2016a) provided evidence that RS504393 decreased pain-related behavior in rats following chronic constriction injury by reducing microglial activation and spinal upregulation of CCL2 and CCR2.…”

Section: Introductionmentioning

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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“…Nucleus pulposus-induced mechanical allodynia is attenuated by treatment with the CCR2 antagonist RS504393 in radicular neuropathic pain. RS504393 decreased lipopolysaccharide-evoked upregulation of the CCL2 and CCR2 expression and protein level in primary microglial cell cultures [103]. Mice lacking CCR2 showed substantially less hypersensitivity to mechanical stimulation after nerve injury but showed a normal response in acute pain [101].…”

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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Direct and indirect pharmacological modulation of CCL2/CCR2 pathway results in attenuation of neuropathic pain — In vivo and in vitro evidence

Cited by 52 publications

References 82 publications

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat

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

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

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