CC‐chemokine ligand 4/macrophage inflammatory protein‐1β participates in the induction of neuropathic pain after peripheral nerve injury

Abstract

Background: Neuropathic pain is caused by neural damage or dysfunction and neuropathic pain-related symptoms are resistant to conventional analgesics. Neuroinflammation due to the cytokine-chemokine network may play a pivotal role in neuropathic pain. We demonstrate that macrophage inflammatory protein-1b (MIP-1b) participates in neuropathic pain. Methods: Mice received partial sciatic nerve ligation (PSL), and tactile allodynia and thermal hyperalgesia were assessed by von Frey test and Hargreaves test, respectively. Agents were administered into the region surrounding the sciatic nerve (SCN). Results: Using reverse transcription polymerase chain reaction, the mRNA expressions of MIP-1b and its receptor (CC-chemokine receptor 5; CCR5) in the injured SCN were up-regulated after PSL. MIP-1b immunoreactivity was localized in macrophages and Schwann cells and increased in the injured SCN on day 1. PSL-induced tactile allodynia on days 4 to 7 was prevented by the administration of MIP-1b neutralizing antibody (anti-MIP-1b; on days 0, 3 and 6). PSL-induced up-regulations of inflammatory cytokine-chemokine mRNAs in the injured SCN were suppressed with anti-MIP-1b treatment on day 7. Administration of CCR5 antagonist, D-alapeptide T-amide (on days 0, 3 and 6) prevented tactile allodynia and thermal hyperalgesia on days 4 to 14. Single administration of recombinant mouse MIP-1b (rmMIP-1b) elicited tactile allodynia. Moreover, rmMIP-1b increased the mRNA expression of inflammatory mediators in the SCN on day 1 after administration. Conclusions: These results suggest that MIP-1b is a novel key mediator, and the peripheral MIP-1b-CCR5 axis contributes to neuropathic pain. Therefore, investigation of this cascade might be a validated approach for the elucidation of neuropathic pain mechanisms.

Altered expression of glial markers, chemokines, and opioid receptors in the spinal cord of type 2 diabetic monkeys

“…The up-regulation of these chemokine ligands (e.g., central CCL2 and CCL3, peripheral CCL4) has been separately shown in rodents with chronic pain [25, 40–42]. The present study is the first to document that these three chemokine systems are simultaneously up-regulated in diabetic primates and that neuroinflammation appears to be permanent in primates with chronic disease.…”

Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats

“…Among the CCR5 ligands, CCL3 and CCL4 appear to be important in neuropathic pain development. Using neutralizing antibodies, Saika et al (2012) showed that CCL3 contributes to the progress of thermal hyperalgesia and tactile allodynia, unlike CCL4, which contributes mainly to tactile allodynia. In 2010, the upregulation of CCL3 in macrophages and Schwann cells in a murine partial sciatic nerve ligation model and the parallel the development of pain was documented (Kiguchi et al, 2010).…”

Mechanism for Increased Expression of UGT2B in the Liver of Mice with Neuropathic Pain

“…When a nerve is injured, histamine, inflammatory cytokines, and chemokines are released from mast cells located in the damaged nerve, inducing the activation and accumulation of neutrophils and macrophages to the nerve site. Subsequently, inflammatory cytokines and chemokines released from the accumulated cells sensitize the primary sensory nerves, 1,2) increasing the release of pain transmitters from the primary sensory nerve endings, resulting in an unusual enhancement of the effect of the pain transmitters on secondary sensory nerves. 3,4) The effect of pain transmitters on secondary sensory nerves is further augmented by the activation of microglia, [5][6][7][8][9] a type of glia cell, in the spinal cord.…”