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Chronic inflammatory pain is a common clinical disease that tends to be associated with negative emotions such as anxiety and depression. The anterior cingulate cortex (ACC) is involved in pain and pain-related anxiety, and γ-aminobutyric acid (GABA)-ergic interneurons play an important role in chronic pain and anxiety. Electroacupuncture (EA) has good analgesic and antianxiety effect, but the underlying mechanisms have not yet been fully elucidated. In this study, we established a chronic inflammatory pain model and observed that this model induced anxiety-like behaviors and decreased the numbers of parvalbumin (PV) and somatostatin (SOM) positive cells. Activation of PV but not SOM interneurons by chemogenetic techniques alleviated anxiety-like behaviors and pain sensation. EA treatment improved pain sensation, anxiety-like behaviors and increased the number of PV- positive cells in the ACC, but did not affect on the number of SOM-positive cells in the ACC. Moreover, specific inhibition of PV interneurons by chemogenetic methods reversed the analgesic and antianxiety effects of EA. These results suggest that EA ameliorates chronic inflammatory pain and pain-related anxiety by upregulating PV but not SOM interneurons in the ACC.

Purpose Chronic inflammatory pain is a common condition in the clinic, and the underlying mechanism is not being completely understood. Various studies have demonstrated that central and peripheral sensitization and synaptic plasticity could play crucial functions in chronic inflammatory pain. Moreover, families of monocarboxylate transporters (MCTs) are closely related to cellular metabolism and synaptic plasticity, and it is also reported that MCTs participate in chronic inflammatory pain. Nevertheless, there is a probability of the engaging role of MCT 1 is in chronic inflammatory pain, but its specific cellular level mechanism is yet to be investigated. In our study, we hypothesized that MCT 1 in the spinal dorsal horn plays an important part in chronic inflammatory pain. Methods In experiment A, rats were gone through nociceptive behavioral testing at 1 d day before and 1 d, 3 d, and 7 d after completing complete Freund’s adjuvant (CFA) injection. The specimens collected for detecting MCT 1 by Western blotting. In experiment B, rats were randomly divided into four groups. Intrathecal injection of MCT 1 inhibitor and nociceptive behavioral tests were performed 1 d day before and 1 d, 3 d, 7 d, 14 d, and 21 d after CFA injection. MCT 1 and p-ERK levels in spinal dorsal horn were measured by Western blotting, and GFAP in spinal dorsal horn was detected by immunofluorescence. Results The expression of MCT 1 in the spinal dorsal horn was increased during chronic inflammatory pain in rats. The intrathecal injection of an MCT 1 inhibitor evidently diminished the expression of MCT 1 and GFAP in the spinal dorsal horn, and the behavioral nociceptive responses were also attenuated. Meanwhile, the expression of p-ERK was also decreased by the intrathecal injection of an MCT 1 inhibitor. Conclusion Our results indicate that MCT 1 very likely play a critical role in regulating chronic inflammatory pain and may influence the regulation of synaptic plasticity via ERK in the spinal dorsal horn of rats.

Background Liver X receptors (LXRs), including LXRα and LXRβ, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXRβ expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated. Methods The deficit of LXR isoform and analgesic effect of LXR activation by GW3965 were evaluated using the mouse model of CIP induced by hindpaw injection of complete Freund’s adjuvant (CFA). The mechanisms involved in GW-mediated analgesic effects were analyzed with immunohistochemical methods, ELISA, co-immunoprecipitation (Co-IP), Western blot, and electrophysiological recording. The epigenetic regulation of LXRβ expression was investigated by chromatin immunoprecipitation, quantitative real-time PCR, and sequencing. Results We revealed that CFA insult led to LXRβ reduction in ACC, which was associated with upregulated expression of histone deacetylase 5 (HDAC5), and knockdown of LXRβ by shRNA led to thermal hyperalgesia. Co-IP showed that LXRβ interacted with NF-κB p65 physically. LXRβ activation by GW3965 exerted analgesic effects by inhibiting the nuclear translocation of NF-κB, reducing the phosphorylation of mitogen-activated protein kinases (MAPKs) in ACC, and decreasing the promoted input-output and enhanced mEPSC frequency in ACC neurons after CFA exposure. In vitro experiments confirmed that HDAC5 triggered histone deacetylation on the promoter region of Lxrβ, resulting in downregulation of Lxrβ transcription. Conclusion These findings highlight an epigenetic mechanism underlying LXRβ deficits linked to CIP, and LXRβ activation may represent a potential novel target for the treatment of CIP with an alteration in inflammation responses and synaptic transmission in ACC. Electronic supplementary material The online version of this article (10.1186/s12974-019-1507-3) contains supplementary material, which is available to authorized users.

Chronic pain is a pathological developing course of pain. In clinic, an objective indicator is needed for diagnosing and better controlling chronic pain. The abnormal neural responses in chronic pain are reflected by multiple event-related potentials (ERPs) in time, frequency and location domain respectively. However, multiple changes in ERPs are not applicable in clinic. So, the principal feature covered the most informative changes extracted from these three domains of ERP during the development of chronic pain is needed. In the present study, a parallel factor analysis (PARAFAC) method was employed to extract time-frequency-channel features of laser evoked potential (LEP) simultaneously from rats with chronic inflammatory pain. Results showed that the main feature of LEP in channel domain locates in the frontal brain region in rats with chronic inflammatory pain while in the parietal brain region in control rats. In the frequency domain, the main frequency of LEP was significantly higher in chronic inflammatory pain rats than that in control rats. These findings indicate that the frontal region with higher frequency response to nociceptive information is the principal feature in the chronic pain state. Our study provided not only a principal feature of LEP but also a promising strategy for chronic pain which is potential for clinic application.

Nitric oxide (NO) is a gaseous molecule implicated both in vascular tone and nociceptive transmission. The capillary blood supply to the dorsal root ganglia (DRG) is unique because it is highly permeable to several low and high molecular-weight compounds. This anatomical situation leads to a potential role of endothelial nitric oxide synthase (eNOS) in inflammatory nociception, which is not well established. Therefore, we examined the role of eNOS in DRG in a murine chronic inflammatory pain model induced by complete Freund’s adjuvant using L-N5-(1-iminoethyl)ornithine (L-NIO), a potent inhibitor of eNOS activity. Pain state was examined using a behavioral test. The expression of eNOS, platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF) was examined by immunofluorescence. In control animals, CD31 was detected in vessels; VEGF was localized both in vessels and neurons while a weak eNOS immunopositivity was detected in both vessels and in neurons. Under inflammatory pain conditions, eNOS, CD31 and VEGF immunopositivity increased. Administration of L-NIO significantly attenuated thermal hyperalgesia by 24 h and decreased eNOS activity and CD31 immunopositivity by 7 days. VEGF was unaffected. Our results show that eNOS plays a nociceptive role in the early phases of inflammation while in the later phases it may be involved in neurotrophic support.