Intra-CA1 Administration of Minocycline Alters the Expression of Inflammation-Related Genes in Hippocampus of CCI Rats.

Abstract

Neuropathic pain is a chronic pain condition that is usually induced by peripheral nerve injury. Recent reports suggest that the inflammation-related cytokines accumulation in dorsal root ganglion, dorsal spinal cord, hippocampus, thalamus, and somatosensoric cortex are paralleled by pain responses in different animal models of neuropathic pain (Al-Amin et al., 2011; Sun et al., 2016; Chang et al., 2018; Liu et al., 2018). In the chronic constriction injury (CCI) and the spared nerve injury models of neuropathic pain in rats, an increase in interleukin 1 beta (IL-1β), interleukin 6 (IL-6), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) was observed in most brain regions (Al-Amin et al., 2011). The overproduction of tumor necrosis factor-α (TNF-α) may regulate synaptic plasticity in the rat hippocampus through microglia-dependent mechanism after spared nerve injury of the sciatic nerve (Liu et al., 2017). However, it is not clear whether other inflammation-related neuroactive substances will be affected after microglia activation in the rat hippocampus after peripheral nerve injury. It is clear that many kinds of toll-like receptors (TLRs) are expressed in the hippocampus and act as a type of pattern-recognition receptor that participate in inflammatory responses. TLR1 expression in the hippocampus was increased in the neurons, microglia, and astrocytes in seizure mice (Wang et al., 2015). TLR (2, 3, 4, 7, and 9) expression was upregulated in the hippocampus of restraint stressed rats (Timberlake et al., 2018). TLR2 and TLR4 in the rat hippocampus are related to the lipopolysaccharide (LPS)-induced neuron cell death (He et al., 2013; Henry et al., 2014). That TLR3-induces the increased expression of IL-1β in the rat hippocampus was suggested by Henry et al. (2014). TLR8, expressed in most regions of the brain, is associated with injury and neurite outgrowth (Ma et al., 2006). It is well known that TLR-dependent signaling is often associated with the overproduction and release of inflammatory cytokines in many different types of cells. However, the relationship between the changes of TLRs expression and microglia activation in hippocampus of CCI rats is not known. Previous studies reveal that chemokine production is enhanced in some neuroimmunological diseases accompanied by pathological pain (Cartier et al., 2005). CXCL13 is obviously upregulated in the spinal cord after spinal nerve ligation and induces astrocyte activation via its receptor CXCR5 (Zhang et al., 2017). Chemokine CCL2 (C-C motif ligand 2) in the rostral ventromedial medulla is related to the descending pain facilitation in nerve-injured rats (Guo et al., 2012). Expression of chemokines CCL2 and CCL3 was increased in the thalamus and hippocampus after severe spinal cord injuries (Knerlich-Lukoschus et al., 2011). The overproduction of IL-1β and CCL2 was found in the hippocampus of CCI rats (Fiore and Austin, 2018). Moreover, Lanfranco et al. reported that CCL5 gene expression was found in neurons and glial cells in the rat hippocampus (Lanfranco et al., 2018). However, no evidence directly addresses the relationship between microglia activation and chemokine accumulation in neuropathic hypersensitivity. It is clear that minocycline is an important modulator of the immune response and easily permeates the blood-brain barrier (Stolp et al., 2007; Vonder Haar et al., 2014). Clinically, minocycline can be administered by the intravenous route in patients with traumatic brain injury (Rojewska et al., 2014). More recent evidence suggest that minocycline is effective at reducing the spontaneous pain behavior in animal models of neuropathic pain, and that means it appears to be a promising analgesic drug (LeBlanc et al., 2011; Rojewska et al., 2014). In the present study, minocycline is applied to identify what inflammation-related genes at the hippocampus are closely related to the increased microglia activity in CCI-induced neuropathic pain rats.