Roles of Gr-1+Leukocytes in Postincisional Nociceptive Sensitization and Inflammation

Abstract

Background Neutrophils are one of the predominant immune cells migrating to surgical wound edges initially. They produce mediators both associated with supporting (interleukin [IL]-1β, C5a) and reducing (opioid peptides) pain. Studies demonstrate neutrophil depletion/blockade reduces nociceptive sensitization after nerve injury and carrageenan administration, but enhance sensitization in Complete Freund's Adjuvant inflammation. This research identifies the contribution of infiltrating neutrophils to incisional pain and inflammation. Methods Antibody-mediated Gr1+ neutrophil depletion preceded hind paw incisions. Sensitization to mechanical and thermal stimuli, effects on edema and local levels of IL-1β and C5a were measured. Local effects of C5a or IL-1 receptor antagonists, PMX53 and Anakinra on sensitization after neutrophil depletion were examined. Groups of 4–8 mice were used. Results Anti-Gr1 antibody depleted >90% of circulating and infiltrating skin neutrophils after incision. Neutrophil depletion did not change magnitude or duration of mechanical hypersensitivity in incised mice. However, paw edema was significantly reduced and heat hypersensitivity was slightly increased in depleted animals. In depleted animals IL-1β levels were half of controls 24 h after incision, while C5a levels were elevated in both. Prominent IL-1β immunohistochemical staining of epidermis was seen in both groups. PMX53 and Anakinra reduced incisional mechanical and heat nociceptive sensitization to the same extent regardless of neutrophil depletion. Conclusions Neutrophil-derived IL-1β and C5a do not appear to contribute critically to peri-incisional nociceptive signaling. Other sources of mediators like epidermal cells may need to be considered. Controlling inflammatory activation of resident cells in epidermis/deeper structures may show therapeutic efficacy in reducing pain from surgical incisions.

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

“…Neutrophils secrete many proinflammatory mediators but also produce opioid peptides that might reduce pain. This dichotomy is evident in the literature, with studies showing that these cells can increase (53)(54)(55) or decrease (56, 57) hypersensitivity, whereas others have shown no effect (58,59) in various models of inflammatory pain. Our results suggest a lack of any major contribution for these cells to pain, at least under our conditions and in other models in which clear depletion was demonstrated.…”

“…Two studies (54, 60) used a similar antibody-mediated neutrophil depletion paradigm in an incisional wound. Sahbaie et al (54) found only a minor effect in thermal latency and no change in mechanical threshold. Carreira et al, meanwhile, saw a dramatic reduction in mechanical hypersensitivity with antibody treatment, but this could have been a result of i.v.…”

Peripheral Nerve Block Facilitates Acute Inflammatory Responses Induced by Surgical Incision in Mice

“…3C and 5). Sahbaie et al 22 previously reported that the depletion of Gr-1 + neutrophils in the incised paw, associated with IL-1β levels half those of the controls 24 hours after incision, did not alter the magnitude or duration of mechanical hypersensitivity, indicating that the increase in Gr-1 + PMNs and expression of IL-1β in peripheral tissue might contribute less to the development of postoperative pain.…”

Curcumin Treatment Attenuates Pain and Enhances Functional Recovery after Incision

“…26 The method described by Hargreaves et al modified for mice was used to determine heat sensitivity. [27][28][29] After acclimation on a temperature-controlled glass platform (23.5°C) in a plastic enclosure with the same dimensions as above, the hindpaw was presented with a beam of light from the heat source. To prevent tissue damage, a 15-second cutoff was used.…”