Abstract
The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47phox, a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.
Highlights
In inflammation leukocyte subpopulations may play different roles in the generation of hyperalgesia
Similar development of inflammatory hyperalgesia and transient receptor potential vannilloid 1 (TRPV1) responsiveness in Dark Agouti (DA) compared to Wistar rats
The mechanical thresholds in DA rats were similar after complete Freund’s adjuvant induced (CFA) treatment compared to Wistar rats (Fig. 2A, B), while the decrease in thermal nociceptive thresholds after i.pl. injection of CFA was less pronounced in DA rats compared to Wistar rats (Fig. 2C, D)
Summary
In inflammation leukocyte subpopulations may play different roles in the generation of hyperalgesia. Intraplantar injection of the neutrophilic chemokine CXCL2/3 (macrophage inflammatory protein, MIP-2) leads to a selective accumulation of neutrophils. In contrast to complete Freund’s adjuvant induced (CFA) inflammation with similar numbers of neutrophils in the tissue, CXCL2/3 induces no mechanical or thermal hyperalgesia [1]. In the early phase of CFA inflammation, neutrophils tonically release opioid peptides resulting in basal analgesia, which could counterbalance proalgesic effects [2]. Other cell populations appear to be responsible for inflammatory hyperalgesia. Monocytes and macrophages are major contributors to inflammatory infiltrate in later phases of inflammation [3]
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