The Analgesic Effects Of Boswellic Acid In Neuropathic Pain And Synergistic Antinociceptive Interactions Between Fospropofol And Alfentanil

Part I: The analgesic effects of Boswellic acid in neuropathic painBackground: Neuropathic pain is an intractable clinical problem. However, the cellular mechanisms underlying neuropathic pain have yet to be fully elucidated. Many drugs have been applied in the clinic such as tricyclic anti-depressants, anti-epileptics, and opioids but fail to provide adequately pain relief accompany with unacceptable side effects.So it is important to explore novel drugs and strategies on neuropathic pain treatment. In recent years, it has been increasingly recognized that the glial cells(astrocytes and microglia)play a critical role in the development and maintenance of neuropathic pain. Frankincense is a traditional herbal medicine for the treatment of inflammatory diseases, the main medicinal ingredient of frankincense is boswellic acid(BA). However, whether BA produces protective effects to alleviate neuropathic pain is not clear yet, and the underlying mechanisms of anti-nociceptive effects of BA on neuropathic pain are also need to be explored.Methods: Behavioral tests were conducted to confirm the effects of BA on mechanical allodynia and heat allodynia. Immunofluorescence was applied for detecting the expression of astrocytic specific marker glial fibrillary acidic protein(GFAP) and the expression and localization of SNI-induced spinal p JNK in the spinal dorsal horn. Western blot was used for quantifying the variations of GFAP and p JNK expression after different treatment. ELISA was used for quantifying the variations of IL- 6, IL-1β, TNF-α and MCP-1.Results: Behavioral data showed that BA inhibited SNI-induced allodynia, however, immunohistochemistry showed that SNI induced astrocytic activation was suppressed by BA. Using quantitative Western blot analysis, our report showed that BA down-regulated GFAP expression, suggesting inhibition of SNI-induced astrocytic activation. ELISA results showed that BA down-regulated IL- 6, IL-1β, TNF-α and MCP-1.The results showed that SNI-induced p JNK up-regulation in the ipsilateral spinal dorsal horn. BA attenuated SNI-induced mechanical allodynia and spinal astrocytic JNK activation in a dose-dependent manner.Conclusions: We conclude from results that BA could alleviate SNI-induced neuropathic pain via the JNK pathway.Part II: Synergistic antinociceptive interactions between fospropofol and alfentanilBackground: Currently, combined several anaesthetic has been adopted to achieve ideal clinical anesthesia effects. Combined anesthesia in order to be able to produce a synergistic effect when several drugs simultaneously, such as more rapid induction of anesthesia, anesthesia was maintained more stable, less adverse reactions, and more secure applications. Propofol, an iv sedative-hypnotic agent with rapid onset and recovery, is widely used to induce and maintain general anaesthesia. However, its lipid-based formulation has disadvantages such as emulsion instability, high lipid intake during longterm administration, dose-related respiratory depression and injection pain. Fospropofol is a water-soluble phosphorylated prodrug, which can be hydrolyzed in vivo to release active propofol, formaldehyde and phosphate within a few minutes after the iv administration. Fospropofol may provide an improved safety and efficacy profile and may be clinically useful when rapid onset of action is not necessary and a more prolonged effect is desired. The goal of this study was to define the pharmacological interaction of fospropofol with alfentanil. With the help of isobolographic analysis, we evaluated the analgesic effect of fospropofol–alfentanil combination on thermally noxious and acute inflammatory stimuli in mice.Methods: The effects of fospropofol, alfentanil and their combinations were examined in the formalininduced paw inflammatory hyperalgesia, the hot-plate test and the tail-flick test in mice. In the three models, dose–response curves were established and their respective ED50(50% effective dose) values were determined separately for each agent. Fixed-ratio combinations of fospropofol and alfentanil(1,1/2,1/4,1/8) were tested for their combined antinociceptive effects, and the type of interaction was determined by the isobolographic analysis.Results: Fospropofol, alfentanil and their combination produced a dose-dependent prolonged the latency of withdrawal. In the three models, isobolographic analysis revealed a significant synergistic interaction between fospropofol and alfentanil. The ED50 value for the drug combination was significantly lower than the theoretical additive value(p < 0.05).Conclusions: The results demonstrate that fospropofol and alfentanil provide synergistic antinociceptive interactions. The observed synergistic interaction between fospropofol and alfentanil are indicative of the effectiveness of the combination treatment in pain management and should be explored in the future.