Qiu

Central administration of C-X-C chemokine receptor type 4 antagonist alleviates the development and maintenance of peripheral neuropathic pain in mice.

Aim To explore the roles of C-X-C chemokine receptor type 4 (CXCR4) in spinal processing of neuropathic pain at the central nervous system (CNS). Methods Peripheral neuropathic pain (PNP) induced by partial sciatic nerve ligation (pSNL) model was assessed in mice. Effects of a single intrathecal (central) administration of AMD3100 (intrathecal AMD3100), a CXCR4 antagonist, on pain behavior and pain-related spinal pathways and molecules in the L3-L5 spinal cord segment was studied compare to saline treatment. Results Rotarod test showed that intrathecal AMD3100 did not impair mice motor function. In pSNL-induced mice, intrathecal AMD3100 delayed the development of mechanical allodynia and reversed the established mechanical allodynia in a dose-dependent way. Moreover, intrathecal AMD3100 downregulated the activation of JNK1 and p38 pathways and the protein expression of p65 as assessed by western blotting. Real-time PCR test also demonstrated that substance P mRNA was decreased, while adrenomedullin and intercellular adhesion molecule mRNA was increased following AMD3100 treatment. Conclusion Our results suggest that central (spinal) CXCR4 is involved in the development and maintenance of PNP and the regulation of multiple spinal molecular events under pain condition, implicating that CXCR4 would potentially be a therapeutic target for chronic neuropathic pain.

Over-expression of astrocytic ET-1 attenuates neuropathic pain by inhibition of ERK1/2 and Akt(s) via activation of ETA receptor.

A differential role of endothelin-1 (ET-1) in pain processing has recently been suggested. However, the function of central ET-1 in neuropathic pain (NP) has not been fully elucidated to date. We report here the action of endogenous central ET-1 in sciatic nerve ligation-induced NP (SNL-NP) in a transgenic animal model that over-expresses ET-1 in the astrocytes (GET-1 mice). We hypothesized that the over-expression of astrocytic ET-1 would exert anti-allodynic and anti-hyperalgesic effects in NP, as demonstrated by mechanical threshold and plantar withdrawal latency using the von Frey filament and heat stimuli. In our animal model, GET-1 mice showed an increase in the withdrawal threshold and latency in response to the mechanical and thermal stimuli, respectively, in pain behavior tests after SNL. ET-1 and endothelin type A receptor (ETA-R) levels were increased significantly in L4-L6 segments of the spinal cord (ipsilateral to SNL) of GET-1 mice at 7 and 21days after surgery. Moreover, intrathecal administration of a specific ETA-R antagonist, BQ-123, attenuated the anti-allodynic and anti-hyperalgesic phenotype in GET-1 mice. The effects of BQ-123 on the mRNA expression of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and protein kinase B/serine protein kinase (Akt(s)) were assessed in the ipsilateral L4-L6 segments harvested 30min after BQ-123 administration on day 7 after surgery. Phosphorylation of ERK1/2 and Akt(s) in the ipsilateral spinal cord of GET-1 mice was reduced following SNL, whereas no reduction was observed after intrathecal injection of BQ-123. In conclusion, our results showed that the xover-expression of astrocytic ET-1 reduced SNL-induced allodynia and hyperalgesia by inhibiting the activation of ERK1/2 and Akt(s) via the ETA-R-mediated pathway.

Endocannabinoid activation of CB1 receptors contributes to long-lasting reversal of neuropathic pain by repetitive spinal cord stimulation

Spinal cord stimulation (SCS) has been shown to be effective in the management of certain neuropathic pain conditions, however, the underlying mechanisms are incompletely understood. In this study, we investigated repetitive SCS in a rodent neuropathic pain model, revealing long‐lasting and incremental attenuation of hyperalgesia and a mechanism of action involving endocannabinoids.

Effects of intra‐operative maintenance of general anaesthesia with propofol on postoperative pain outcomes – a systematic review and meta‐analysis

Propofol is used both for induction and maintenance of anaesthesia. Recent evidence shows that propofol has analgesic properties. This meta‐analysis evaluated differences in postoperative analgesia between general anaesthetic maintenance with intravenous propofol and inhalational anaesthetics. Fourteen trials met inclusion criteria and were included. Our outcomes were pain scores 2 and 24 h after surgery. No significant difference in pain scores was found at 2 h after surgery (Hedges g (95% CI) −0.120 (−0.415–0.175) (p = 0.425). Propofol was associated with a statistically significant, albeit marginal, reduction in pain scores 24 h after surgery (Hedges g (95% CI) −0.134 (−0.248 to −0.021) (p = 0.021). Data were insufficient to allow a meaningful analysis regarding 24‐h morphine‐equivalent consumption. Propofol was associated with reduced postoperative nausea and vomiting (relative risk (95%CI) 0.446 (0.304–0.656) (p < 0.0001). In conclusion, this meta‐analysis suggests that propofol improves postoperative analgesia compared with inhalational anaesthesia 24 h after surgery, with a lower incidence of nausea and vomiting.

Effects of Repeated Central Administration of Endothelin Type A Receptor Antagonist on the Development of Neuropathic Pain in Rats

Endothelin-1 (ET-1) predominates in the endothelin family effectively in vascular tone control, mitogenesis, and neuromodulation. Its receptors are widespread in the central nervous system (CNS) associated with endogenous pain control, suggesting an important role of ET-1 in central pain processing. This study aimed to evaluate the effect of central ET-1 on the development of neuropathic pain behaviour by repeated intrathecal administration of endothelin type A receptor (ETAR) antagonist (BQ-123) in a sciatic nerve ligation (SNL) animal model. BQ-123 was administered intrathecally to rats at dosages 15 μg, 20 μg, 25 μg, and 30 μg, daily for 3 days. Mechanical allodynia was assessed daily 30 minutes before/after injection, 1 hour after injection of BQ-123 from post-SNL day 4 to day 6, and once on day 7 (without BQ-123 administration) before rats were sacrificed. Increasing trends of mechanical threshold were observed, and they reached significance at all dosages on post-SNL day 7 (P < 0.05 at dosage 15 μg and P < 0.001 at dosages 20 μg, 25 μg, and 30 μg) in comparison to control group. BQ-123 at dosage 30 μg showed the most stable and significant mechanical threshold rise. Repeated central administration of BQ-123 alleviated mechanical allodynia after SNL. Our results provide insight into the therapeutic strategies, including timing, against neuropathic pain development with ETAR antagonist.

Effects of Intra-Operative Total Intravenous Anaesthesia with Propofol versus Inhalational Anaesthesia with Sevoflurane on Post-Operative Pain in Liver Surgery: A Retrospective Case-Control Study

Background Patients receiving total intravenous anesthesia (TIVA) with propofol have been shown to experience less postoperative pain. We evaluated the post-operative analgesic effects of propofol compared with sevoflurane maintenance of anesthesia in liver surgery. This study was registered at ClinicalTrials.gov (NCT02179437). Methods In this retrospective study, records of patients who underwent liver surgery between 2010 and 2013 were reviewed. Ninety-five patients anesthetized with propofol TIVA were matched with 95 patients anesthetized with sevoflurane. Numeric pain rating scale (NRS) pain scores, postoperative morphine consumption, side effects and patients’ satisfaction with pain relief were evaluated. Results The TIVA group reported lower NRS pain scores during coughing on postoperative days 1 and 2 but not 3 (p = 0.0127, p = 0.0472, p = 0.4556 respectively). They also consumed significantly less daily (p = 0.001 on day 1, p = 0.0231 on day 2, p = 0.0004 on day 3), accumulative (p = 0.001 on day 1, p<0.0001 on day 2 and p = 0.0064 on day 3) and total morphine (p = 0.03) when compared with the sevoflurane group. There were no differences in total duration of intravenous patient controlled analgesia (PCA) morphine use and patient satisfaction. No difference was found in reported side effects. Conclusion Patients anesthetized with propofol TIVA reported less pain during coughing and consumed less daily, accumulative and total morphine after liver surgery.

Preventive Treatment with Ketamine Attenuates the Ischaemia-Reperfusion Response in a Chronic Postischaemia Pain Model

Ischemia and inflammation may be pathophysiological mechanisms of complex regional pain syndrome (CRPS). Ketamine has proposed anti-inflammatory effects and has been used for treating CRPS. This study aimed to evaluate anti-inflammatory and analgesic effects of ketamine after ischaemia-reperfusion injury in a chronic postischaemia pain (CPIP) model of CRPS-I. Using this model, ischemia was induced in the hindlimbs of male Sprague-Dawley rats. Ketamine, methylprednisolone, or saline was administered immediately after reperfusion. Physical effects, (oedema, temperature, and mechanical and cold allodynia) in the bilateral hindpaws, were assessed from 48 hours after reperfusion. Fewer (56%) rats in the ketamine group developed CPIP at the 48th hour after reperfusion (nonsignificant). Ketamine treated rats showed a significantly lower temperature in the ischaemic hindpaw compared to saline (P < 0.01) and methylprednisolone (P < 0.05) groups. Mechanical and cold allodynia were significantly lower in the ischaemic side in the ketamine group (P < 0.05). Proinflammatory cytokines TNF-α and IL-2 were significantly lower at the 48th hour after reperfusion in ketamine and methylprednisolone groups, compared to saline (all P < 0.05). In conclusion, immediate administration of ketamine after an ischaemia-reperfusion injury can alleviate pain and inflammation in the CPIP model and has potential to treat postischaemic pain.

An Audit of Changes in Outcomes of Acute Pain Service: Evolution Over the Last 2 Decades.

AbstractAcute pain services (APS) have evolved over time. Strategies nowadays emphasize multimodal analgesic regimes using a combination of nonopioid adjuvant analgesic drugs, peripheral nerve blocks, and local anaesthetic wound infiltration where appropriate. APS should be assessed over time to evaluate changes in outcomes which form the basis for future development.In this audit, data of patients under APS care in Queen Mary hospital, Hong Kong, between 2009 and 2012 were analyzed and compared with data from a previous audit between 1992 and 1995. The use of patient-controlled analgesia (PCA) was increased (from 69.3% to 86.5%, P < 0.001), while the use of epidural analgesia reduced (from 25.3% to 8.3%, P < 0.001) significantly. Although postoperative pain scores did not improve, PCA opioid consumption and the incidence of analgesia-related side effects were significantly less (all P < 0.001). More patients graded their postoperative analgesic techniques used as good when the results from these 2 audit periods were compared (P < 0.001 and P = 0.001 for PCA and epidural analgesia, respectively). In conclusion, there has been a change in analgesic management techniques, but there has been no improvement in overall pain relief. While changes over time have led to improvement in important parameters such as the incidence of side effects and patient satisfaction, further and continuous efforts and improvements are warrant to reduce acute pain relief and suffering of the patients after the surgery.

[EXPRESS] Propofol produces preventive analgesia via GluN2B-containing NMDA Receptor/ERK1/2 Signaling Pathway in a rat model of inflammatory pain

Propofol, an intravenous anesthetic, has been shown to offer superior analgesic effect clinically. Whether propofol has preventive analgesic property remains unexplored. The present study investigated the antinociceptive effect of propofol and underlying molecular and cellular mechanisms via pre-emptive administration in a formalin-induced inflammatory pain model in rats. Male adult Sprague–Dawley rats were randomly allocated into four groups: naïve (Group Naïve), formalin injection only (Group Formalin), and formalin injection at 30 min (Group P-30 min) or 2 h (Group P-2 h) after intravenous infusion of propofol (0.6 mg kg−1 min−1) for 1 h. Nociceptive responses and protein expression of phosphorylated- or pan-GluN2B, ERK1/2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in the spinal dorsal horn were evaluated. Alteration of intracellular Ca2+ concentration induced by N-methyl-D-aspartate (NMDA) receptor agonists with or without pre-treatment of propofol was measured using fluorometry in SH-SY5Y cells while neuronal activation in the spinal dorsal horn by immunofluorescence. Pre-emptive propofol reduced pain with a delayed response to formalin and a reduction in hypersensitivity that lasted at least for 2 h. The formalin-induced activation of spinal GluN2B and ERK1/2 but not p38 or c-Jun N-terminal kinase was also diminished by propofol treatment. Preconditioning treatment with 3 µM and 10 µM of propofol inhibited Ca2+ influx mediated through NMDA receptors in SH-SY5Y cells. Propofol also reduced the neuronal expression of c-Fos and p-ERK induced by formalin. This study shows that pre-emptive administration of propofol produces preventive analgesic effects on inflammatory pain through regulating neuronal GluN2B-containing NMDA receptor and ERK1/2 pathway in the spinal dorsal horn.