Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-γ (PPARγ), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPARγ in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain hypersensitivity by a PPARγ tight junction protein-dependent mechanism during the course of dextran sodium sulfate (DSS)-induced intestinal inflammation. The DSS-induced colitis model was generated in C57BL/6 mice. Changes in colitis induced the injury of intestinal mucosal barrier and hyperalgesia after a 6-day treatment of pioglitazone (25 mg/kg, IP injection) were assessed through immunofluorescent, hematoxylin and eosin (H&E) staining, western blot analysis, and determination of paw withdrawal mechanical threshold. A significant reduction of paw withdrawal mechanical threshold occurred after DSS treatment. Follow-up data showed that systematic administration of PPARγ agonist pioglitazone ameliorated the DSS-induced colitis and the development of colitis-associated hyperalgesia by repairing the intestinal mucosal barrier. The tight junction proteins ZO-1 and Claudin-5 were upregulated by PPARγ signaling, which in turn promoted the improvement of intestinal barrier function. Moreover, pioglitazone inhibited phosphorylation of ERK and NF-κB in the colon and decreased the levels of inflammatory cytokines in both colon spine tissues. Furthermore, systemically pioglitazone treatment inhibited the activation of microglia and astrocytes, as well as DSS-induced phosphorylation of NR2B subunit in spinal cord, which was correspondingly consistent with the pain behavior. Pioglitazone ameliorates DSS-induced colitis and attenuates colitis-associated mechanical hyperalgesia, with improving integrity of the intestinal mucosal barrier by directly upregulating tight junction proteins. The PPARγ-tight junction protein signaling might be a potential therapeutic target for the treatment of colitis-associated chronic pain.

/pdf/pioglitazone-attenuates-experimental-colitis-associated-ucvyqo5e1p.pdf

Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction.

Withdrawal from systemic opioids can induce long-term potentiation (LTP) at spinal C-fibre synapses ("opioid-withdrawal-LTP"). This is considered to be a cellular mechanism underlying opioid withdrawal-induced hyperalgesia, which is a major symptom of the opioid withdrawal syndrome. Opioids can activate glial cells leading to the release of proinflammatory mediators. These may influence synaptic plasticity and could thus contribute to opioid-withdrawal-LTP. Here, we report a sexual dimorphism in the mechanisms of morphine-withdrawal-LTP in adult rats. We recorded C-fibre-evoked field potentials in the spinal cord dorsal horn from deeply anaesthetised male and female rats. In both sexes, we induced a robust LTP through withdrawal from systemic morphine infusion (8 mg·kg-1 bolus, followed by a 1-hour infusion at a rate of 14 mg·kg-1·h-1). This paradigm also induced mechanical hypersensitivity of similar magnitude in both sexes. In male rats, systemic but not spinal application of (-)naloxone blocked the induction of morphine-withdrawal-LTP, suggesting the involvement of descending pronociceptive pathways. Furthermore, we showed that in male rats, the induction of morphine-withdrawal-LTP required the activation of spinal astrocytes and the release of the proinflammatory cytokines tumour necrosis factor and interleukin-1. In striking contrast, in female rats, the induction of morphine-withdrawal-LTP was independent of spinal glial cells. Instead, blocking µ-opioid receptors in the spinal cord was sufficient to prevent a facilitation of synaptic strength. Our study revealed fundamental sex differences in the mechanisms underlying morphine-withdrawal-LTP at C-fibre synapses: supraspinal and gliogenic mechanisms in males and a spinal, glial cell-independent mechanism in females.

Fundamental sex differences in morphine withdrawal-induced neuronal plasticity.

The anterior cingulate cortex (ACC) plays a key role in regulating mood in animals, especially anxiety, and is also a brain region that is indispensable to pain perception. Postoperative anxiety is closely related to the experience of pain. Remifentanil is a commonly used surgical analgesic. The mechanism of supraspinal hyperalgesia caused by remifentanil remains unclear. We used animal models to simulate postoperative hyperalgesia and studied the GluR1 AMPA receptor subunit in the ACC using western blots and immunocytochemistry. Behavioral tests were used to estimate anxiety levels. We found no significant change in GluR1 levels before and after hyperalgesia, whereas phosphorylation of GluR1Ser845 was significantly increased after hyperalgesia. Double staining for c-Fos, widely used as a marker of neural activation, and Arc, which facilitates GluR1 endocytosis, revealed that neural activation increased and the expression of Arc decreased after hyperalgesia. Local injection of a protein kinase A inhibitor (H89) in the ACC effectively blocked the phosphorylation of GluR1Ser845 and alleviated the hyperalgesia and anxiety shown in the behavioral tests. Double staining revealed no significant change in c-Fos or Arc levels after the administration of H89. Local injection of ibotenic acid caused damage to the ACC, following which remifentanil did not induce hyperalgesia or anxiety. These results lead us to conclude that the ACC is a critical hub for remifentanil-induced hyperalgesia (RIH) and RIH-related anxiety and that regulating the phosphorylation of GluR1Ser845 may modulate RIH and anxiety. Anxiety may be an influential factor contributing to individual differences in RIH occurrence.

The Mechanism of Hyperalgesia and Anxiety Induced by Remifentanil: Phosphorylation of GluR1 Receptors in the Anterior Cingulate Cortex.

Roles of Phosphorylation of N-Methyl-d-Aspartate Receptor in Chronic Pain

Background: Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in ex vivo experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury. Methods: Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 µg). Cerebral reactive oxygen species (ROS) production, cell death, in situ labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18. Results: In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1 levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice. Conclusions: In vivo exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated.

/pdf/beneficial-effects-of-remifentanil-against-excitotoxic-brain-536fcn333k.pdf

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice.

Experimental studies have demonstrated that modulation of N-Methyl-D-Aspartate (NMDA) receptor subunits 1 and 2 (NR1 and NR2) through phosphorylation can affect remifentanil induced postoperative o...

Enhancement of spinal dorsal horn neuron NMDA receptor phosphorylation as the mechanism of remifentanil induced hyperalgesia: Roles of PKC and CaMKII

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Enhancement of spinal dorsal horn neuron NMDA receptor phosphorylation as the mechanism of remifentanil induced hyperalgesia: Roles of PKC and CaMKII