Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice

TY - JOUR

T1 - Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice

AU - Staniland, Amelia A

AU - Clark, Anna K

AU - Wodarski, Rachel

AU - Sasso, Oscar

AU - Maione, Francesco

AU - D'Acquisto, Fulvio

AU - Malcangio, Marzia

PY - 2010/8

Y1 - 2010/8

N2 - The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. Naive CX3CR1 KO mice had normal responses to acute noxious stimuli. However, KO mice showed deficits in inflammatory and neuropathic nociceptive responses. After intraplantar zymosan, KO mice did not display thermal hyperalgesia, whereas mechanical allodynia developed fully. In the partial sciatic nerve ligation model of neuropathic pain, both mechanical allodynia and thermal hyperalgesia were less severe in KO mice than in wild-types (WT). Dorsal horn Iba1 immunostaining and phosphorylation of p38 MAPK increased after injury in WT controls but not in KO animals. In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models.

AB - The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. Naive CX3CR1 KO mice had normal responses to acute noxious stimuli. However, KO mice showed deficits in inflammatory and neuropathic nociceptive responses. After intraplantar zymosan, KO mice did not display thermal hyperalgesia, whereas mechanical allodynia developed fully. In the partial sciatic nerve ligation model of neuropathic pain, both mechanical allodynia and thermal hyperalgesia were less severe in KO mice than in wild-types (WT). Dorsal horn Iba1 immunostaining and phosphorylation of p38 MAPK increased after injury in WT controls but not in KO animals. In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models.

KW - Animals

KW - CX3C Chemokine Receptor 1

KW - Calcium-Binding Proteins

KW - Chemokine CX3CL1

KW - Disease Models, Animal

KW - Female

KW - Hyperalgesia

KW - Inflammation Mediators

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Microfilament Proteins

KW - Microglia

KW - Peripheral Nervous System Diseases

KW - Posterior Horn Cells

KW - Receptors, Chemokine

KW - Sciatic Neuropathy

KW - Spinal Cord

KW - Up-Regulation

KW - p38 Mitogen-Activated Protein Kinases

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/j.1471-4159.2010.06837.x

DO - 10.1111/j.1471-4159.2010.06837.x

M3 - Article

C2 - 20524966

SN - 0022-3042

VL - 114

SP - 1143

EP - 1157

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

IS - 4

ER -