Neutrophils: are they hyperalgesic or anti-hyperalgesic?

Cunha, Thiago M.; Verri, Waldiceu A.

doi:10.1189/jlb.0406244

Cited by 16 publications

(10 citation statements)

References 14 publications

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“…Neutrophils are normally the first cell type to infiltrate damaged tissue and are essential for immunity and resistance to pathogens [24]. However, the role of neutrophils in pain has been debated [25], [26]. Our data demonstrating that neutrophils contribute to pain correlate well with published results showing that inhibition of the neutrophil chemoattractant leukotriene B 4 reduced hyperalgesia and neutrophil influx into the joint in a pre-clinical arthritis model [27].…”

Section: Discussionsupporting

confidence: 84%

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

et al. 2014

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Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1−/− animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1−/− mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain.

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Section: Discussionsupporting

confidence: 84%

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

et al. 2014

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“…Furthermore, selective and transient neutropenia delays thermal hyperalgesia following neuropathic sciatic transection (Perkins and Tracey 2000) and attenuates NGF-induced nociception (Bennett et al 1998, Bennett 1999, as well as allergen-evoked nociception (Lavich et al 2006). However, although pain is a common clinical complication of intradermal PMN accumulation (Heuft et al 2004, Marchand et al 2005, selective intradermal PMN recruitment by CXC chemokine ligands 1 and 2/3 does not induce mechanical allodynia or thermal hyperalgesia (Rittner et al 2006, also see Cunha and Verri, 2006), in agreement with personal observations following intradermal PMN injection in the rat's hindpaw. As emerging clinical data point to an association between neuropathic pain conditions and neuroinflammation (Watkins and Maier 2002), evidence that PMN might counteract inflammatory hyperalgesia by releasing opioid peptides should also be taken into consideration (Brack et al 2004, Rittner et al 2006).…”

Section: Discussionsupporting

confidence: 55%

Activated polymorphonuclear cells promote injury and excitability of dorsal root ganglia neurons

Shaw

Owolabi

Bagley

et al. 2008

Experimental Neurology

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Therapies aimed at depleting or blocking the migration of polymorphonuclear leukocytes (PMN or neutrophils) are partially successful in the treatment of neuroinflammatory conditions and in attenuating pain following peripheral nerve injury or subcutaneous inflammation. However, the functional effects of PMN on peripheral sensory neurons such as dorsal root ganglia (DRG) neurons are largely unknown. We hypothesized that PMN are detrimental to neuronal viability in culture and increase neuronal activity and excitability. We demonstrate that isolated peripheral PMN are initially in a relatively resting state but undergo internal oxidative burst and activation by an unknown mechanism within 10 min of co-culture with dissociated DRG cells. Co-culture for 24 h decreases neuronal count at a threshold<0.4:1 PMN:DRG cell ratio and increases the number of injured and apoptotic neurons. Within 3 min of PMN addition, fluorometric calcium imaging reveals intracellular calcium transients in small size (<25 microm diam) and large size (>25 microm diam) neurons, as well as in capsaicin-sensitive neurons. Furthermore, small size isolectin B4-labeled neurons undergo hyperexcitability manifested as decreased current threshold and increased firing frequency. Although co-culture of PMN and DRG cells does not perfectly model neuroinflammatory conditions in vivo, these findings suggest that activated PMN can potentially aggravate neuronal injury and cause functional changes to peripheral sensory neurons. Distinguishing the beneficial from the detrimental effects of PMN on neurons may aid in the development of more effective drug therapies for neurological disorders involving neuroinflammation, including painful neuropathies.

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“…For instance, it was demonstrated that during inflammation induced by CFA, the stimulation of recruited PMN with IL-1␤, corticotropin release factor, or even with stress stimulus produces an antinociceptive effect dependent on PMN production of opioids [39 -41]. These contradictions might be explained by the differences in the inflammatory models [42].…”

Section: Discussionmentioning

confidence: 99%

Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2

Guerrero

Verri

Cunha

et al. 2007

Journal of Leukocyte Biology

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Leukotriene B4 (LTB4) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB4-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1-9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO(-/-)) or by the selective antagonist of the LTB(4) receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO(-/-) mice. The hypernociceptive role of LTB4 was confirmed further by the demonstration that joint injection of LTB4 induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB4 production. Investigating the mechanism underlying LTB4 mediation of zymosan-induced hypernociception, LTB4-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 mug, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO(-/-) mice. The production of LTB4 induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE2 induced by LTB4. Therefore, besides reinforcing the role of endogenous LTB4 as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB4-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB4-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB4 synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.

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Neutrophils: are they hyperalgesic or anti-hyperalgesic?

Cited by 16 publications

References 14 publications

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

Activated polymorphonuclear cells promote injury and excitability of dorsal root ganglia neurons

Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2

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