Anterior Insular-Nucleus Accumbens Pathway Controls Refeeding-Induced Analgesia Under Chronic Inflammatory Pain Condition

Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 hr refeeding after 24hr fasting (i.e. refeeding) attenuates pain behavior under chronic inflammatory pain conditions. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Herein, we demonstrate that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in a modified Complete Freund’s Adjuvant (CFA)-induced chronic inflammatory pain condition, which was reversed by refeeding. We also found that refeeding reduced the enhanced excitability of aICCamKII–NAcSD2R projecting neurons in this CFA model. Besides, chemogenetic inhibition of aICCamKII–NAcSD2R neural circuit suppressed chronic pain behavior while activation of this circuit reversed refeeding-induced analgesia. Thus, the present study suggests that aICCamKII – NacSD2R neural circuit mediates refeeding-induced analgesia, thereby serving as a potential therapeutic target to manage chronic pain.

Chronic THC vapor rescues inflammation-related thermal hyperalgesia and causes cell type-specific modifications in vlPAG neurons

To reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain and/or as a strategy for reducing opioid drug dosage and duration of treatment (i.e., so-called opioid-sparing effects). Previous preclinical work has shown robust anti-hyperalgesic effects of systemic THC and acute anti-hyperalgesic effects of vaporized THC. Here, we used a vapor inhalation model in rats to test chronic THC vapor inhalation effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., periaqueductal gray [PAG]) neuronal function, in adult male rats with chronic inflammatory pain. We report that chronic THC vapor inhalation produces a robust anti-hyperalgesic effect in rats with chronic inflammatory pain, and that this effect persists 24 hours after cessation of THC exposure. We demonstrate that chronic THC vapor inhalation also modulates intrinsic and synaptic properties of ventrolateral PAG (vlPAG) neurons, including reductions in action potential firing rate and reductions in spontaneous inhibitory synaptic transmission, and that these effects occur specifically in neurons that respond to current input with a delayed firing phenotype. Finally, we show that the suppressive effect of the bath-applied mu-opioid receptor (MOR) agonist DAMGO on synaptic inhibition in the vlPAG is enhanced in slices taken from rats with a history of chronic THC vapor inhalation. Collectively, these data show that chronic THC vapor inhalation produces lasting attenuation of thermal hyperalgesia and reduces synaptic inhibition in the vlPAG of rats with chronic inflammatory pain.

Anxiolytic effect of GABAergic neurons in the anterior cingulate cortex in a rat model of chronic inflammatory pain

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABAAR agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABAAR antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.

Electroacupuncture Ameliorates Chronic Inflammatory Pain-Related Anxiety by Activating PV Interneurons in the Anterior Cingulate Cortex

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.

Effects of Gastrodin on Analgesia and Inhibition of Ferroptosis

Background: Gastrodin possesses low toxicity and a broad range of pharmacological activities and exhibits beneficial effects in neurological diseases. This study investigated the effects of gastrodin (GAS) on analgesic, anti-inflammatory, anxiolytic and inhibition of ferroptosis. Materials and Methods: The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund’s adjuvant (CFA). After GAS treatment, Thermal hyperalgesia test, Mechanical allodynia test, Elevated plus-maze (EPMT) and Open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1 and PTGS2 were measured by RT-qPCR. Results: In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold was increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4 and H0-1, as well as decreased the expression of PTGS2 in a dose-dependent manner. Conclusion: GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It maybe exhibit potential neuroprotective effects through inhibition of ferroptosis.

Pharmacological Blockade of PPARα Exacerbates Inflammatory Pain-Related Impairment of Spatial Memory in Rats

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that exist in three isoforms: PPARα, PPARβ/δ and PPARγ. Studies suggest that the PPAR signalling system may modulate pain, anxiety and cognition. The aim of the present study was to investigate whether endogenous signalling via PPARs differentially modulates innate anxiety responses and mnemonic function in the presence and absence of inflammatory pain. We examined the effects of intraperitoneal administration of GW6471 (PPARα antagonist), GSK0660 (PPARβ/δ antagonist), GW9662 (PPARγ antagonist), and N-palmitoylethanolamide (PEA) on rat behaviour in the elevated plus maze (EPM), open field (OF), light-dark box (LDB), and novel object recognition (NOR) tests in the presence or absence of chronic inflammatory pain. Complete Freund’s Adjuvant (CFA)-injected rats exhibited impaired recognition and spatial mnemonic performance in the NOR test and pharmacological blockade of PPARα further impaired spatial memory in CFA-treated rats. N-oleoylethanolamide (OEA) levels were higher in the dorsal hippocampus in CFA-injected animals compared to their counterparts. The results suggest a modulatory effect of CFA-induced chronic inflammatory pain on cognitive processing, but not on innate anxiety-related responses. Increased OEA-PPARα signalling may act as a compensatory mechanism to preserve spatial memory function following CFA injection.