Yu’e Sun

Intrathecal injection of JWH015 attenuates remifentanil-induced postoperative hyperalgesia by inhibiting activation of spinal glia in a rat model.

BACKGROUND:Hyperalgesia and neuroinflammation are associated with glia, which consists of macroglia and microglia. In this study, we used a selective cannabinoid receptor type 2 (CB2) agonist JWH015 to investigate remifentanil-induced postoperative hyperalgesia. METHODS:Mechanical allodynia and thermal hyperalgesia after postoperative hyperalgesia and intrathecal injection of JWH015 were assessed by the paw withdrawal mechanical threshold and paw withdrawal thermal latency tests. We used immunohistochemistry and immunoblotting to investigate the effect of JWH015 on CB2 receptor, NR2B subunits, activated glial cells, and proinflammatory cytokine expression in rats after remifentanil-induced postoperative hyperalgesia. RESULTS:Postoperative hyperalgesia was induced by intraoperative infusion of remifentanil. Glial cells were activated, and expression levels of several genes were significantly increased, including interleukin 6, tumor necrosis factor &agr;, CB2, and the NR2B subunit phosphorylated at Tyr-1472 (p-NR2B). Intrathecal injection of JWH015 significantly inhibited glial cell activation, suppressed expression of interleukin 6, tumor necrosis factor &agr;, and p-NR2B, and stimulated CB2 expression, thus attenuating postoperative hyperalgesia. However, these phenomena were abolished in the group that was preadministered with AM630. CONCLUSIONS:The activation of glia, the production of proinflammatory cytokines, and the expression of CB2 and p-NR2B in the spinal dorsal horn increase significantly during the process of remifentanil-induced hyperalgesia. These changes can be regulated by pretreatment with JWH015, which may be the main mechanism underlying the antihyperalgesia effects of JWH015.

Positive feedback regulation between microRNA-132 and CREB in spinal cord contributes to bone cancer pain in mice

cAMP response element‐binding protein (CREB)‐dependent gene expression plays an important role in central sensitization. CREB‐regulated transcription coactivator 1 (CRTC1) dramatically increase CREB‐mediated transcriptional activity. microRNA‐132 (miR‐132), which is highly CREB‐responsive, functions downstream from CREB/CRTC1 to mediate activity‐dependent synaptic plasticity and in turn loops back to amplify CREB/CRTC1 signalling. This study aimed to investigate the positive feedback regulation between miR‐132 and CREB in spinal cord in the maintenance of bone cancer pain.

The activation of spinal astrocytes contributes to preoperative anxiety-induced persistent post-operative pain in a rat model of incisional pain

Preoperative anxiety, a clinically significant problem for many patients undergoing surgery, is associated with prolonged and exacerbated post‐operative pain. To date, the mechanisms of preoperative anxiety‐induced persistent post‐operative pain remain unclear. The present study aimed to provide a rat model of preoperative anxiety‐induced persistent post‐operative pain using the single‐prolonged stress (SPS) procedure to induce preoperative anxiety‐like behaviours, and to explore the role of spinal astrocytes in this phenomenon.

Mas-Related Gene (Mrg) C Activation Attenuates Bone Cancer Pain via Modulating Gi and NR2B.

Objective This study is to investigate the role of Mas-related gene (Mrg) C in the pathogenesis and treatment of bone cancer pain (BCP). Methods BCP mouse model was established by osteosarcoma cell inoculation. Pain-related behaviors were assessed with the spontaneous lifting behavior test and mechanical allodynia test. Expression levels of MrgC, Gi, and NR2B in the spinal cord were detected with Western blot analysis and immunohistochemistry. Results Pain-related behavior tests showed significantly increased spontaneous flinches (NSF) and decreased paw withdrawal mechanical threshold (PWMT) in mouse models of BCP. Western blot analysis showed that, compared with the control group and before modeling, all the expression levels of MrgC, Gi, and NR2B in the spinal cord of BCP mice were dramatically elevated, which were especially increased at day 7 after operation and thereafter, in a time-dependent manner. Moreover, the treatment of MrgC agonist BAM8-22 significantly up-regulated Gi and down-regulated NR2B expression levels, in the spinal cord of BCP mice, in a time-dependent manner. On the other hand, anti-MrgC significantly down-regulated Gi expression, while dramatically up-regulated NR2B expression, in the BCP mice. Similar results were obtained from the immunohistochemical detection. Importantly, BAM8-22 significantly attenuated the nociceptive behaviors in the BCP mice. Conclusion Our results indicated the MrgC-mediated Gi and NR2B expression alterations in the BCP mice, which might contribute to the pain hypersensitivity. These findings may provide a novel strategy for the treatment of BCP in clinic.

Hippocampal activation of microglia may underlie the shared neurobiology of comorbid posttraumatic stress disorder and chronic pain.

The high comorbidity rates of posttraumatic stress disorder and chronic pain have been widely reported, but the underlying mechanisms remain unclear. Emerging evidence suggested that an excess of inflammatory immune activities in the hippocampus involved in the progression of both posttraumatic stress disorder and chronic pain. Considering that microglia are substrates underlying the initiation and propagation of the neuroimmune response, we hypothesized that stress-induced activation of hippocampal microglia may contribute to the pathogenesis of posttraumatic stress disorder-pain comorbidity. We showed that rats exposed to single prolonged stress, an established posttraumatic stress disorder model, exhibited persistent mechanical allodynia and anxiety-like behavior, which were accompanied by increased activation of microglia and secretion of pro-inflammatory cytokines in the hippocampus. Correlation analyses showed that hippocampal activation of microglia was significantly correlated with mechanical allodynia and anxiety-like behavior. Our data also showed that both intraperitoneal and intra-hippocampal injection of minocycline suppressed single prolonged stress-induced microglia activation and inflammatory cytokines accumulation in the hippocampus, and attenuated both single prolonged stress-induced mechanical allodynia and anxiety-like behavior. Taken together, the present study suggests that stress-induced microglia activation in the hippocampus may serve as a critical mechanistic link in the comorbid relationship between posttraumatic stress disorder and chronic pain. The novel concept introduces the possibility of cotreating chronic pain and posttraumatic stress disorder.

Intraoperative electroacupuncture relieves remifentanil-induced postoperative hyperalgesia via inhibiting spinal glial activation in rats

Background Accumulating studies have suggested that remifentanil, the widely-used opioid analgesic in clinical anesthesia, can activate the pronociceptive systems and enhance postoperative pain. Glial cells are thought to be implicated in remifentanil-induced hyperalgesia. Electroacupuncture is a complementary therapy to relieve various pain conditions with few side effects, and glial cells may be involved in its antinociceptive effect. In this study, we investigated whether intraoperative electroacupuncture could relieve remifentanil-induced postoperative hyperalgesia by inhibiting the activation of spinal glial cells, the production of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases. Methods A rat model of remifentanil-induced postoperative hyperalgesia was used in this study. Electroacupuncture during surgery was conducted at bilateral Zusanli (ST36) acupoints. Behavior tests, including mechanical allodynia and thermal hyperalgesia, were performed at different time points. Astrocytic marker glial fibrillary acidic protein, microglial marker Iba1, proinflammatory cytokines, and phosphorylated mitogen-activated protein kinases in the spinal cord were detected by Western blot and/or immunofluorescence. Results Mechanical allodynia and thermal hyperalgesia were induced by both surgical incision and remifentanil infusion, and remifentanil infusion significantly exaggerated and prolonged incision-induced pronociceptive effects. Glial fibrillary acidic protein, Iba1, proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α), and phosphorylated mitogen-activated protein kinases (p-p38, p-JNK, and p-ERK1/2) were upregulated after surgical incision, remifentanil infusion, and especially after their combination. Intraoperative electroacupuncture significantly attenuated incision- and/or remifentanil-induced pronociceptive effects, spinal glial activation, proinflammatory cytokine upregulation, and phosphorylated mitogen-activated protein kinase upregulation. Conclusions Our study suggests that remifentanil-induced postoperative hyperalgesia can be relieved by intraoperative electroacupuncture via inhibiting the activation of spinal glial cells, the upregulation of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases.

Anti-nociceptive effects of caloric restriction on neuropathic pain in rats involves silent information regulator 1

Background: Caloric restriction (CR) increases both average and maximum lifespan, retards physiological signs of ageing, and delays the onset of several diseases and may mediate neuropathic pain. Neuropathic pain seriously affects the quality of life of patients. In this study, we investigated whether CR exerts anti‐nociceptive effects on neuropathic pain, and probed its potential mechanisms. Methods: Adult rats were divided into two dietary groups: an ad libitum (AL)‐fed group and a CR group, which was provided with 60% of the food intake of AL rats for 6 weeks. The effects of 6‐week CR on pain behaviour and neuro‐inflammation induced by chronic constriction injury of the sciatic nerve were evaluated. Results: Rats subjected to a CR diet had reduced hypersensitivity to mechanical and thermal stimuli after nerve‐constriction injury. CR increased the silent information regulator 1 (SIRT1) expression, and suppressed the nerve‐constriction‐induced production of mitochondrial‐derived reactive oxygen species and activation of nuclear factor kappa B accompanied by suppression of mature interleukin‐1&bgr; production in the ipsilateral spinal cord dorsal horn. The inhibition of SIRT1 reversed the effects of caloric restriction on pain behaviours. Moreover, CR decreased the phosphorylation of N‐methyl‐d‐aspartate receptor subunits and the mitogen‐activated protein kinase family, decreased the sensory neurone excitability, and inhibited the nerve‐constriction‐induced glial‐cell activation. Conclusions: These results suggest that the effects of CR on pain behaviours in a rat model of nerve injury are via inhibition of excessive neuro‐inflammation induced by the injury. CR may be of benefit in patients with neuropathic pain.