Background: Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP. Methods: We used a skin/muscle incision and retraction (SMIR) model to establish a rat CPSP model. Microglia, CXCR7, and the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways were regulated by intrathecal injections of minocycline (a non-specific microglial inhibitor), AMD3100 (a CXCR7 agonist), and LY294002 (a specific PI3K inhibitor), respectively. Mechanical allodynia was detected with von Frey filaments. The changes in microglia, A1 astrocytes, A2 astrocytes, CXCR7, and PI3K/Akt signaling pathways were examined by enzyme-linked immunosorbent assay (ELISA), western blot, and immunofluorescence. Results: Microglia were found to be activated, with an increase in interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q) in the spinal cord at an early stage after SMIR. On day 14 after SMIR, spinal cord astrocytes were also activated; these were mainly of the A1 phenotype and less of the A2 phenotype. Intrathecal injection of minocycline relieved SMIR-induced mechanical allodynia and reverted the ratio of A1/A2 reactive astrocytes. The expression of CXCR7 and PI3K/Akt signaling was decreased after SMIR, while they were increased after treatment with minocycline. Furthermore, intrathecal injection of AMD3100 also relieved SMIR-induced mechanical allodynia, reverted the ratio of A1/A2 reactive astrocytes, and activated the PI3K/Akt signaling pathway, similar to the effects produced by minocycline. However, intrathecal injection of AMD3100 did not increase the analgesic effect of minocycline. Last, LY294002 inhibited the analgesic effect and A1/A2 transformation induced by minocycline and AMD3100 after SMIR. Conclusion: Our results indicated that microglia induce the transformation of astrocytes to the A1 phenotype in the spinal cord via downregulation of the CXCR7/PI3K/Akt signaling pathway during CPSP. Reverting A1 reactive astrocytes to A2 may represent a new strategy for preventing CPSP.
Morphine tolerance is a classic, challenging clinical
issue. However,
the mechanism underlying this phenomenon remains poorly understood.
Recently, studies have shown that ferroptosis correlates with drug
resistance. Therefore, this study investigated whether spinal cord
ferroptosis contributes to morphine tolerance. C57BL/6 mice were continuously
subcutaneously injected with morphine, with or without the ferroptosis
inhibitor liproxstatin-1. We found that chronic morphine exposure
led to morphine antinociception tolerance, accompanied by loss of
spinal cord neurons, increase in the levels of iron, malondialdehyde,
and reactive oxygen species, and decreases in the levels of superoxide
dismutase. Additionally, inflammatory response and mitochondrial shrinkage,
processes that are involved in ferroptosis, were observed. Simultaneously,
we found that 10 mg/kg of liproxstatin-1 could alleviate iron overload
by balancing transferrin receptor protein 1/ferroportin expression
and attenuate morphine tolerance by increasing glutathione peroxidase
4 levels, while reducing the levels of malondialdehyde and reactive
oxygen species. It also downregulated the expression of extracellularly
regulated protein kinases that had been induced by chronic morphine
exposure. Our results indicate that spinal cord ferroptosis contributes
to morphine tolerance, while liproxstatin-1 attenuates the development
of morphine tolerance. These findings suggest that ferroptosis may
be a potential therapeutic target for morphine tolerance.
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