Neuropathic pain, whose symptoms are characterized by spontaneous and irritation-induced painful sensations, is a condition that poses a global burden. Numerous neurotransmitters and other chemicals play a role in the emergence and maintenance of neuropathic pain, which is strongly correlated with common clinical challenges, such as chronic pain and depression. However, the mechanism underlying its occurrence and development has not yet been fully elucidated, thus rendering the use of traditional painkillers, such as non-steroidal anti-inflammatory medications and opioids, relatively ineffective in its treatment. Astrocytes, which are abundant and occupy the largest volume in the central nervous system, contribute to physiological and pathological situations. In recent years, an increasing number of researchers have claimed that astrocytes contribute indispensably to the occurrence and progression of neuropathic pain. The activation of reactive astrocytes involves a variety of signal transduction mechanisms and molecules. Signal molecules in cells, including intracellular kinases, channels, receptors, and transcription factors, tend to play a role in regulating post-injury pain once they exhibit pathological changes. In addition, astrocytes regulate neuropathic pain by releasing a series of mediators of different molecular weights, actively participating in the regulation of neurons and synapses, which are associated with the onset and general maintenance of neuropathic pain. This review summarizes the progress made in elucidating the mechanism underlying the involvement of astrocytes in neuropathic pain regulation.
The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats.Repeated i.t. morphine treatment was used to induce anti-nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKCε and exchange factor directly activated by cAMP (Epac) were evaluated. Effects of A-317491 (P2X3 antagonist), ε-V1-2 (PKCε inhibitor) and ESI-09 (Epac inhibitor) on mechanical pain thresholds and tail-flick latency after chronic morphine treatment were determined. Co-localization of P2X3 receptor with NeuNs (marker of neuron), IB4 (marker of small DRG neurons), peripherin, PKCε and Epac were performed by double immunofluorescence staining.Chronic morphine time-dependently increased the expression of P2X3 receptor, phosphorylated PKCε and Epac in DRGs. ε-V1-2 prevented chronic morphine-induced expression of P2X3 receptor. ESI-09 decreased the phosphorylation of PKCε and up-regulated expression of Epac after chronic morphine exposure. Mechanical pain thresholds and tail-flick latency showed that A317491, ε-V1-2 and ESI-09 significantly attenuated the loss of morphine's analgesic potency. Morphine-induced P2X3 receptor expression mainly occurred in neurons staining for IB4 and peripherin. Co-localization of P2X3 receptor with PKCε and Epac was demonstrated in the same neurons.Chronic morphine exposure increased the expression of P2X3 receptor, and i.t. P2X3 receptor antagonists attenuated the loss of morphine's analgesic effect. Inhibiting Epac/PKCε signalling was shown to play a significant inhibitory role in chronic morphine-induced P2X3 receptor expression and attenuate morphine-induced tolerance.
Abstract The limited analgesic efficiency of magnesium restricts its application in pain management. Here, we report boron hydride (BH) with ion currents rectification activity that can enhance the analgesic efficiency of magnesium without the risks of drug tolerance or addiction. We synthesize MgB 2 , comprising hexagonal boron sheets alternating with Mg 2+ . In pathological environment, Mg 2+ is exchanged by H + , forming two‐dimensional borophene‐analogue BH sheets. BH interacts with the charged cations via cation‐pi interaction, leading to dynamic modulation of sodium and potassium ion currents around neurons. Additionally, released Mg 2+ competes Ca 2+ to inhibit its influx and neuronal excitation. In vitro cultured dorsal root neurons show a remarkable increase in threshold potential from the normal −35.9 mV to −5.9 mV after the addition of MgB 2 , indicating potent analgesic effect. In three typical pain models, including CFA‐induced inflammatory pain, CINP‐ or CCI‐induced neuropathic pain, MgB 2 exhibits analgesic efficiency approximately 2.23, 3.20, and 2.0 times higher than clinical MgSO 4 , respectively, and even about 1.04, 1.66, and 1.95 times higher than morphine, respectively. The development of magnesium based intermetallic compounds holds promise in addressing the non‐opioid medical need for pain relief.
Abstract The limited analgesic efficiency of magnesium restricts its application in pain management. Here, we report boron hydride (BH) with ion currents rectification activity that can enhance the analgesic efficiency of magnesium without the risks of drug tolerance or addiction. We synthesize MgB 2 , comprising hexagonal boron sheets alternating with Mg 2+ . In pathological environment, Mg 2+ is exchanged by H + , forming two‐dimensional borophene‐analogue BH sheets. BH interacts with the charged cations via cation‐pi interaction, leading to dynamic modulation of sodium and potassium ion currents around neurons. Additionally, released Mg 2+ competes Ca 2+ to inhibit its influx and neuronal excitation. In vitro cultured dorsal root neurons show a remarkable increase in threshold potential from the normal −35.9 mV to −5.9 mV after the addition of MgB 2 , indicating potent analgesic effect. In three typical pain models, including CFA‐induced inflammatory pain, CINP‐ or CCI‐induced neuropathic pain, MgB 2 exhibits analgesic efficiency approximately 2.23, 3.20, and 2.0 times higher than clinical MgSO 4 , respectively, and even about 1.04, 1.66, and 1.95 times higher than morphine, respectively. The development of magnesium based intermetallic compounds holds promise in addressing the non‐opioid medical need for pain relief.
Background and Purpose Tolerance induced by morphine and other opiates remains a major unresolved problem in the clinical management of pain. There is now good evidence for the importance of MAPKs in morphine‐induced antinociceptive tolerance. A member of the MAPK kinase kinase family, TGF ‐ β activated kinase 1 ( TAK1 ) is the common upstream kinase of MAPKs . Here, we have assessed the involvement of TAK1 in the development of tolerance to morphine‐induced analgesia. Experimental Approach The effects of an antagonist of TAK1 on morphine tolerance were investigated in vivo using the R andall– S elitto test, and the mechanism was investigated using W estern blot and immunohistochemistry. The expression of TAK1 after chronic morphine exposure was also evaluated in vitro by immunohistochemistry. Key Results Chronic intrathecal morphine exposure up‐regulated protein levels and phosphorylation of spinal TAK1 . TAK1 immunoreactivity was co‐localized with the neuronal marker NeuN . Intrathecal administration of 5Z ‐7‐oxozeaenol ( OZ ), a selective TAK1 inhibitor, attenuated the loss of morphine analgesic potency and morphine‐induced TAK1 up‐regulation. Furthermore, OZ decreased the up‐regulated expression of spinal p38 and JNK after repeated morphine exposure. In vitro studies demonstrated that sustained morphine treatment induced TAK1 up‐regulation, which was reversed by co‐administration of OZ . A bolus injection of OZ showed some reversal of established morphine antinociceptive tolerance. Conclusions and Implications TAK1 played a pivotal role in the development of morphine‐induced antinociceptive tolerance. Modulation of TAK1 activation by the selective inhibitor OZ in the lumbar spinal cord may prove to be an attractive adjuvant therapy to attenuate such tolerance.
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