CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization

Abstract

Pathological pain conditions can be triggered after peripheral nerve injury and/or inflammation. It is associated with plasticity of nociceptive pathway in which pain is prolonged even after healing of the injured tissue. Generally combinations of analgesic drugs are not sufficient to achieve selective palliation from chronic pain, besides causing a greater number of side effects. In order to identify novel alternatives for more effective treatments, it is necessary to clarify the underlying mechanisms of pathological pain. It is well established that there are two main components in pathological pain development and maintenance: (i) primary sensory neuron sensitization (peripheral sensitization), and (ii) central sensitization. In both components cytokines and chemokines act as key mediators in pain modulation. CXCL1 is a chemokine that promote both nociceptor and central sensitization via its main receptor CXCR2, which is a promising target for novel analgesic drugs. Here, we reviewed and discussed the role of the CXCL1/CXCR2 signaling axis in pathological pain conditions triggered by either peripheral inflammation or nerve injury.

Introduction

As a physiological component, pain acts as an alarm to withdraw from an injurious condition to reduce tissue damage. However, in pathological pain conditions, such as chronic pain, this unpleasant experience may start after tissue damage that remains subsequent to tissue healing, even in the absence of stimulation potentially dangerous. In such circumstance, pain becomes harmful and is detrimental to pursuance of an acceptable quality of life by an individual. Chronic pain is commonly triggered by nerve injury and chronic peripheral inflammation. These insults induce the release of neurotransmitters, lipid mediators, fragments of the complement system, neurotrophic factors, cytokines and chemokines in both the central (CNS) and peripheral nervous system (PNS). Together, these and other components mediate the “leukocyte-neuron–glia multi-directional communication” which leads to peripheral and central sensory neurons sensitization. These interactions generally result in genesis and maintenance of pathological pain. Therefore, nerve injury or peripheral inflammation induces activation and proliferation of glial cells, leukocyte recruitment and increases neuronal excitability in the PNS and CNS, and both are involved in the nociceptive transmission changes (Eijkelkamp et al., 2012, Ma and Quirion, 2006). The elucidation of how these cells and mediators interact with each other can provide better targets for drug development of more effective and selective analgesics. Among all these mediators, chemokines are emerging as attractive targets. They act peripherally and centrally in modulating nociceptive transmission and seem to be important to switch from physiological to pathological pain conditions (Cunha et al., 2005, Gao and Ji, 2010, Ji et al., 2014, Souza et al., 2013, Zarpelon et al., 2016).

Chemokines are small chemotactic cytokines which can control the trafficking and migratory behavior of peripheral immune and/or glial cells (Bajetto et al., 2001, Cross and Woodroofe, 1999, Tanabe et al., 1997). However, their participation in induction and maintenance of pathological pain states, such as inflammatory and neuropathic pain, is not restricted to their chemotactic activities. Glial and neuronal cells can also be activated by chemokines, which contributes to peripheral sensitization and neuroplasticity, whereby they modulate the pain process. Some chemokines have a prominent role in pain modulation, such as CX3CL1, CCL2, CXCL1, CXCL8, CCL7 and CCL21 (Biber and Boddeke, 2014, Imai et al., 2013, Ji et al., 2014, Ke et al., 2016, Ren and Dubner, 2010, Souza et al., 2013, Wang et al., 2009). In accordance, new drugs targeting chemokine receptors have been developed to treat diseases, including inflammatory and neuropathic pain, which are undergoing evaluation in pre-clinical (Cunha et al., 2008a, Lopes et al., 2016) or clinical trials (Horuk, 2009). CXCL1 is one of the chemokines with significant role in pain modulation, which can be produced both peripherally and centrally. The described effects of CXCL1 to mediate inflammatory and neuropathic pain development occur through activation of its principal cognate receptor, C-X-C chemokine receptor type 2 (CXCR2), which is expressed by PNS and CNS neurons. Herein, we review and discuss what is known about the role of CXCL1/CXCR2 signaling pathways in the pathophysiology of pain focusing on its mechanisms in peripheral and central nervous system.