Search

Aims: Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain‐related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. Methods: Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain‐induced anxiety‐like behaviors. Adeno‐associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC‐DRN circuit in chronic pain‐induced anxiety‐like behaviors and investigated whether EA could reverse chronic pain‐induced dysfunctions of the rACC‐DRN circuit and anxiety‐like behaviors. Results: We found that chemogenetic activation of the rACC‐DRN circuit alleviated CFA‐induced anxiety‐like behaviors, while chemogenetic inhibition of the rACC‐DRN circuit resulted in short‐term CFA‐induced anxiety‐like behaviors. Further research revealed that the development of CFA‐induced anxiety‐like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII‐DRN5‐HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII‐DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII‐DRN5‐HT circuit alleviates anxiety‐like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII‐DRNGABA circuit altered CFA chronic pain‐evoked anxiety‐like behaviors in rats. More importantly, we found that EA could reverse chronic pain‐induced changes in the activity of rACC CaMKII neurons and DRN 5‐HTergic neurons and that chemogenetic inhibition of the rACCCaMKII‐DRN5‐HT circuit blocked the therapeutic effects of EA on chronic pain‐induced anxiety‐like behaviors. Conclusions: Our data suggest that the reversal of rACCCaMKII‐DRN5‐HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain‐induced anxiety‐like behaviors. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammatory pain (CIP) frequently coincides with depression among patients. The onset and development of pain and depression are associated with altered neural synaptic plasticity. Electroacupuncture (EA) can effectively relieve CIP and depression. However, the underlying mechanisms have not been fully illustrated. Objective: To explore whether EA can relieve CIP and depression by regulating hippocampal synaptic plasticity, and the present study offers foundational evidence for the efficacy of EA in treating CIP‐related depression (CIPD). Methods: Rats were divided into four groups: 0.9% normal saline group, complete Freund's adjuvant (CFA) group, CFA + duloxetine group, and CFA + EA group. Pain hypersensitivity was detected by mechanical withdrawal threshold and thermal paw withdrawal latency, and the depression level was gauged using the open field test, the sucrose preference test, and the forced swimming test. The morphology of the hippocampal neurons was observed using Nissl staining. The protein expression levels of synuclein (Syn), postsynaptic density protein‐95 (PSD‐95), brain‐derived neurotrophic factors (BDNFs), tyrosine‐protein kinase B (TrKB), p‐TrkB, cAMP response element binding protein (CREB), and p‐CREB were measured by western blotting and immunofluorescence staining. BDNF and TrkB mRNA expression were detected using quantitative real‐time polymerase chain reaction (PCR) (qRT‐PCR). The content of 5‐hydroxytryptamine (5‐HT) and γ‐aminobutyric acid (GABA) was detected using enzyme‐linked immunosorbent assay, and the glutamic acid (Glu) content was determined using the ultraviolet colorimetry method. The hippocampal neuron ultrastructure was observed using transmission electron microscopy. Results: EA could alleviate CIP and related depressive behaviors as well as protect the hippocampal neuronal structure from damage and regulate 5‐HT/GABA/Glu levels in the hippocampus. Additionally, EA could significantly increase the expression of synapse‐associated proteins such as PSD‐95 and Syn by activating the BDNF/TrKB/CREB signaling pathway. Conclusion: EA improves pain and depressive behaviors in CIPD rats, and the mechanism may be related to synaptic plasticity mediated by the BDNF/TrKB/CREB signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Voltage-gated sodium channels play an essential role in regulating the excitability of nociceptive primary afferent neurones. In particular the tetrodotoxin-sensitive (TTX-S) NaV1.7 and the tetrodotoxin-resistant (TTX-R) NaV1.8 and NaV1.9 channels have been suggested to play a role in inflammatory pain. Previous work has revealed acute administration of inflammatory mediators, such as Freund’s complete adjuvant (FCA) or carrageenan caused an upregulation in the levels of NaV1.7 and NaV1.8 protein in DRG (dorsal root ganglia) tissue up to 4 days post-insult. In the present study, the expression of NaV1.7, NaV1.8 and NaV1.9 was examined over a 28 day timecourse during a rat model of FCA-induced chronic inflammatory joint pain. Using the retrograde tracer Fast Blue (FB) and specific NaV1.7, NaV1.8 and NaV1.9 sodium channel antibodies, immunohistochemical staining techniques were used to study sodium channel expression in a distinct population of L3–L5 knee joint afferent DRGs. In the ganglia, counts were made of positively labelled cells in the FB population. The results demonstrate that, following FCA injection, NaV1.9 expression is upregulated at days 14, 21 and 28 post-FCA, with NaV1.7 and NaV1.8 showing increased channel expression at days 14 and 28. These observations are accompanied by a unilateral joint hypersensitivity in the FCA-injected knee indicated by a behavioural shift in weight distribution measured using an incapacitance tester. The increased presence of these channels suggests that NaV1.7, NaV1.8 and NaV1.9 play a role, at least in part, in the maintenance of chronic inflammatory pain several weeks after the initial insult. [Copyright &y& Elsevier]

Abstract: Neuropeptide-expressing small diameter sensory neurones are thought to be vital in generating inflammatory hyperalgesic responses. Within the dorsal root ganglion (DRG), both the levels of the neuropeptide calcitonin gene-related peptide (CGRP) and the numbers of CGRP-immunoreactive (CGRP-IR) DRG neurones have been shown to increase in a number of acute adjuvant-induced inflammatory pain models. The aim of this study was to look specifically at changes in numbers of CGRP-IR DRG neurones in a chronic model of inflammatory joint pain following complete Freund’s adjuvant (CFA) injection into the rat knee. In this model, there were significant increases in the number of ipsilateral CGRP-IR small DRG neurones at days 1, 16 and 35 following intra-articular CFA, compared to saline-injected sham animals. This correlated with the behavioural readouts of hypersensitivity and knee joint inflammation at the same time points. There was also a significant increase in the number of ipsilateral CGRP-IR medium DRG neurones and contralateral CGRP-IR small DRG neurones at day 1. Following dosing of CFA-injected rats with rofecoxib (Vioxx™) or paracetamol, there was a significant decrease in the number of ipsilateral CGRP-IR small and medium DRG neurones in rofecoxib- but not paracetamol-treated rats. These data also correlated with behavioural readouts where hypersensitivity and knee joint inflammation were significantly reduced by rofecoxib but not paracetamol treatment. In conclusion, these data show that changes in ipsilateral CGRP expression within small DRG neurones are consistent with behavioural readouts in both time course, rofecoxib and paracetamol studies in this model of chronic inflammatory pain. [Copyright &y& Elsevier]