The impact of mouse strain-specific spatial and temporal immune responses on the progression of neuropathic pain.

The present study was designed to investigate the correlation between the spatial and temporal aspects of immune responses and genetic heterogeneity in the progression of peripheral neuropathic pain. To address this issue, we first screened four inbred mouse strains (C57BL/6J, C3H/He, DBA/2, and A/J mice) to identify high- and low-responder strains to mechanical hypersensitivity induced by partial sciatic nerve ligation (pSNL). Among these strains, the C57BL/6J strain showed the highest vulnerability to pSNL-induced mechanical hypersensitivity, whereas the C3H/HeSlc strain was most resistant. C3H/HeSlc mice exhibited a significant increase in CD206-immunoreactivity (anti-inflammatory macrophages) in the dorsal root ganglia (DRG) at 3 and 7 days, and lower Iba1-immunoreactivity (microglia) in the spinal cord from 3 to 14 days after pSNL than C57BL/6J mice. These phenomena might be associated with a decrease in the production of inflammatory factors (interleukin-1ß, interleukin-6, and CX3CL1) in the DRG and the poor responsiveness of spinal microglia (i.e. microglial production of IL1ß, CCL2, and TNFα) against CX3CL1 in C3H/HeSlc mice. Behavioral experiments using bone marrow (BM) chimeric mice derived by crossing C3H/HeSlc and C57BL/6J strains showed that the strength of mechanical hypersensitivity 3 days following pSNL was inversely correlated with the increase in the ratio of anti-inflammatory/pro-inflammatory DRG macrophages, which was based on the BM-derived hematopoietic cells from donor mice. By contrast, the intensity of Iba1-immunoreactivity (microglia) in the spinal cord was dependent on the phenotypes of recipient mice, but not affected by the phenotypes of BM-derived donor hematopoietic cells. These findings suggest that the strain-specific aspects of DRG macrophages and spinal microglia might be related to the early and late phases of pSNL-induced mechanical hypersensitivity, respectively. This study presents a greater understanding of the differences in neuropathic pain among genetically heterogeneous inbred mouse strains, and provides further insights into the spatial and temporal roles of the immune system in the pathogenesis of neuropathic pain.

Colchicine alleviates acute postoperative pain but delays wound repair in mice: roles of neutrophils and macrophages.

Background: Acute postoperative pain is induced by most incisional surgeries and usually resolves with wound repair. However, many patients experience moderate to severe pain despite receiving currently available postoperative pain relief. Accumulating evidence suggests that inflammatory cells, neutrophils, and macrophages infiltrating the wound site contribute to the acute inflammation, pain, and subsequent wound repair. Colchicine is commonly used to relieve pain in gout by inhibiting the infiltration of granulocytes and other motile cells. In this study, we examined the effects of colchicine on acute postoperative pain and wound repair by correlating the infiltration of neutrophils and macrophages in a mouse model of postoperative pain induced by plantar incision. Furthermore, these effects of colchicine were compared with clodronate liposomes, which selectively deplete circulating macrophages. Results: Plantar incision induced mechanical hypersensitivity in the ipsilateral hind paw that peaked one day and lasted for three days after the surgery. Treatment with colchicine significantly attenuated the early infiltration of Gr1-positive cells (neutrophils) around the incision site and mechanical hypersensitivity, which was accompanied with inhibition of the subsequent infiltration of Iba1-positive cells (macrophages) and macrophage polarization toward the proinflammatory M1 phenotype. By contrast, an intravenous injection of clodronate liposomes significantly inhibited the infiltration of macrophages around the incision site but had little effect on the infiltration of neutrophils or mechanical hypersensitivity. Importantly, colchicine treatment significantly delayed wound closure after the incisional surgery, whereas clodronate liposome administration had no effect on wound closure. Conclusion: These results suggest that colchicine can alleviate acute postoperative pain and also enhance the risk of delayed wound repair, which are associated with the suppression of neutrophil and subsequent proinflammatory M1 macrophage infiltration around the incision site, while the involvement of macrophages may be limited.

Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models.

Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2) in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2-knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate-induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain.

[Roles of transient receptor potential melastatin 2 expressed on immune cells in neuropathic pain].

Neuropathic pain is a pathological pain condition that often results from peripheral nerve injury. Several lines of evidence suggest that neuroinflammation mediated by the interaction between immune cells and neurons plays an important role in the pathogenesis of neuropathic pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca(2+)-permeable cation channel that acts as a sensor for reactive oxygen species. Recent evidence suggests that TRPM2 expressed on immune cells plays an important role in immune and inflammatory responses. In this study, we examined the roles of TRPM2 expressed on immune and glial cells in neuropathic pain. TRPM2 deficiency attenuated pain behaviors (mechanical allodynia, thermal hyperalgesia and spontaneous pain behaviors) in various kinds of inflammatory and neuropathic pain, but not in nociceptive pain models. In peripheral nerve injury-induced neuropathic pain models, TRPM2 deficiency diminished infiltration of neutrophils mediated through CXCL2 production from macrophages around the injured peripheral nerve and activation of spinal microglia, suggesting that TRPM2 expressed on macrophages and microglia aggravates peripheral and spinal pronociceptive inflammatory responses. Furthermore, we examined the infiltration of peripheral immune cells into the injured nerve and spinal cord using bone marrow chimeric mice by crossing wildtype and TRPM2-knockout mice. The results suggest that TRPM2 plays an important role in the infiltration of peripheral immune cells, particularly macrophages, into the spinal cord, rather than into the injured nerves. The spinal infiltration of macrophages mediated by TRPM2 may contribute to the pathogenesis of neuropathic pain.