The cytochrome P450 proteins(CYP450s)have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases.CYP26A1,a member of the CYP450 family,carries out the oxidative m...The cytochrome P450 proteins(CYP450s)have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases.CYP26A1,a member of the CYP450 family,carries out the oxidative metabolism of retinoic acid(RA),the active metabolite of vitamin A.Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation(SNL).CYP26A1 was mainly expressed in spinal neurons and astrocytes.HPLC analysis displayed that the content of all-trans-RA(at-RA),the substrate of CYP26A1,was reduced in the spinal cord on day 7 after SNL.Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain.Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine(IL-10)production.The RA receptors RARα,RXRβ,and RXRγwere expressed in spinal neurons and glial cells.The promoter of Il-10 has several binding sites for RA receptors,and at-RA directly increased Il-10 mRNA expression in vitro.Finally,intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia.Collectively,the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation.CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.展开更多
Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies.Astrocytes are the most abundant glial cells in the central nervous system and play important roles in ...Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies.Astrocytes are the most abundant glial cells in the central nervous system and play important roles in different pathological conditions,including chronic pain.Astrocytes regulate nociceptive synaptic transmission and network function via neuron–glia and glia–glia interactions to exaggerate pain signals under chronic pain conditions.It is also becoming clear that astrocytes play active roles in brain regions important for the emotional and memory-related aspects of chronic pain.Therefore,this review presents our current understanding of the roles of astrocytes in chronic pain,how they regulate nociceptive responses,and their cellular and molecular mechanisms of action.展开更多
The unpleasant sensations itch and pain induce distinct behavioral patterns.Although both acute itch and pain serve protective functions,they are different sensory modalities.Itch stimuli lead to the scratching reflex...The unpleasant sensations itch and pain induce distinct behavioral patterns.Although both acute itch and pain serve protective functions,they are different sensory modalities.Itch stimuli lead to the scratching reflex or the desire to scratch,which may be helpful for removing potential irritants.In contrast,pain stimuli lead to withdrawal behaviors but not scratching[1].展开更多
The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitato...The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation(SNL).SNL increased the frequency,but not the amplitude of spontaneous inhibitory postsynaptic currents(sIPSCs),and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs)in the MSNs.SNL also decreased the paired-pulse ratio(PPR)of evoked IPSCs but increased the PPR of evoked EPSCs.Moreover,acute bath application of C–C motif chemokine ligand 2(CCL2)increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs,and especially strengthened the amplitude of N-methyl-D-aspartate receptor(NMDAR)-mediated miniature EPSCs.Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio.Finally,Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression(LTD)in the NAc after SNL.These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.展开更多
基金supported by STI2030-Major Projects(2022ZD0204700)the National Natural Science Foundation of China(32030048,31700899,and 32200817)+1 种基金the Graduate Student Scientific Research Innovation Projects of Jiangsu Province(KYCX18-2397)the Startup Foundation for Doctors of the Affiliated Hospital of Nantong University(Tdb1906).
文摘The cytochrome P450 proteins(CYP450s)have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases.CYP26A1,a member of the CYP450 family,carries out the oxidative metabolism of retinoic acid(RA),the active metabolite of vitamin A.Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation(SNL).CYP26A1 was mainly expressed in spinal neurons and astrocytes.HPLC analysis displayed that the content of all-trans-RA(at-RA),the substrate of CYP26A1,was reduced in the spinal cord on day 7 after SNL.Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain.Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine(IL-10)production.The RA receptors RARα,RXRβ,and RXRγwere expressed in spinal neurons and glial cells.The promoter of Il-10 has several binding sites for RA receptors,and at-RA directly increased Il-10 mRNA expression in vitro.Finally,intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia.Collectively,the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation.CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.
基金supported by the Ministry of Science and Technology of China Brain Initiative Grant(2022ZD0204702)the National Natural Science Foundation of China(32030048 and 32100806)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(21KJB310010).
文摘Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies.Astrocytes are the most abundant glial cells in the central nervous system and play important roles in different pathological conditions,including chronic pain.Astrocytes regulate nociceptive synaptic transmission and network function via neuron–glia and glia–glia interactions to exaggerate pain signals under chronic pain conditions.It is also becoming clear that astrocytes play active roles in brain regions important for the emotional and memory-related aspects of chronic pain.Therefore,this review presents our current understanding of the roles of astrocytes in chronic pain,how they regulate nociceptive responses,and their cellular and molecular mechanisms of action.
基金the National Natural Science Foundation of China(81870874)the Natural Science Foundation of Jiangsu Province,China(BK20170004)Jiangsu Key Laboratory of Neuropsychiatric Diseases(BM2013003)。
文摘The unpleasant sensations itch and pain induce distinct behavioral patterns.Although both acute itch and pain serve protective functions,they are different sensory modalities.Itch stimuli lead to the scratching reflex or the desire to scratch,which may be helpful for removing potential irritants.In contrast,pain stimuli lead to withdrawal behaviors but not scratching[1].
基金Grants from the National Natural Science Foundation of China(32030048,31871064,and 31671091).
文摘The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation(SNL).SNL increased the frequency,but not the amplitude of spontaneous inhibitory postsynaptic currents(sIPSCs),and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs)in the MSNs.SNL also decreased the paired-pulse ratio(PPR)of evoked IPSCs but increased the PPR of evoked EPSCs.Moreover,acute bath application of C–C motif chemokine ligand 2(CCL2)increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs,and especially strengthened the amplitude of N-methyl-D-aspartate receptor(NMDAR)-mediated miniature EPSCs.Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio.Finally,Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression(LTD)in the NAc after SNL.These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.