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

Abstract

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.

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

“…Both the absence of microglial response and neuronal degeneration differentiate chemotherapy-induced allodynia from nerve-injury induced allodynia, which is associated with significant contribution of microglial-neuronal feedback to the chronicity of pain. Another intriguing observation is that, while microglial CX3CR1 receptors contribute to nerve injury-induced allodynia (25), centrally located CX3CR1 receptors are unlikely to participate to VCR-induced allodynia. Therefore, we can rule out a role for central CX3CR1 in VCR-induced allodynia and focus on the CX3CR1-expressing cells in the periphery, the monocyte-macrophage.…”

“…As these mice showed no difference in dorsal horn microglial response compared with that of microglia from WT mice after 2 VCR cycles (Supplemental Figure 8), we can exclude the engagement of CX3CR1 microglial cells in response to VCR treatment. Therefore, even though the CX3CR1 receptor is also expressed by microglia in the CNS and activation of microglial CX3CR1 by neuronal FKN mediates pain facilitation in the spinal cord after peripheral nerve damage (25), centrally located CX3CR1 receptors are not likely to be involved in VCR-induced allodynia.…”

“…Three baseline measurements were made prior to treatment, the average of which is presented. Static mechanical withdrawal thresholds were assessed by applying von Frey filaments (Linton Instruments) to the plantar surface of the hind paw (25,32). Unrestrained animals were acclimatized in acrylic cubicles (8 × 5 × 10 cm) above a wire mesh for up to 60 minutes prior to testing.…”

Fractalkine mediates inflammatory pain through activation of satellite glial cells

“…Therefore, in addition to mediating spinal cord microglia activation (27), fractalkine/ CX3CR1 signaling appears to also be involved in the activation of SGCs after peripheral inflammation and, consequently, in the genesis of inflammatory pain. Accordingly, CX3CR1-deficient mice present reduced inflammatory pain after the peripheral administration of zymosan (28).…”

“…During neuronal stimulation after a nerve lesion, fractalkine is suggested to be cleaved into its soluble form, which can in turn act on CX3CR1-expressing microglia (27). This interaction promotes the activation of microglia, which contributes to the genesis of chronic pain (28,29). This evidence, together with the demonstration that fractalkine is also expressed in the cell bodies of the primary afferent neurons, whereas CX3CR1 expression was found in the SGCs, led us to suggest that the activation of SGCs during peripheral inflammation is dependent on fractalkine/CX3CR1 signaling.…”