Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. N...Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models： ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion （DRG）, which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability （but not spontaneous activity） measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.展开更多
Objective Inflammation at the level of the sensory dorsal root ganglia （DRGs） leads to robust mechanical pain behavior and the local inflammation has direct excitatory effects on sensory neurons including small, pri...Objective Inflammation at the level of the sensory dorsal root ganglia （DRGs） leads to robust mechanical pain behavior and the local inflammation has direct excitatory effects on sensory neurons including small, primarily no- ciceptive, neurons. These neurons express the transient receptor potential vanilloid-1 （TRPV1） channel, which integrates multiple signals of pain and inflammation. The aim of this study was to characterize the regulation of the TRPV1 channel by local DR（] inflammation and by growth-related oncogene （（]RO/KC, systemic name： CXCL1）, a cytokine known to be upregulated in inflamed DRGs. Methods Activation of the TRPV1 receptor with capsaicin was studied with patch clamp methods in acutely isolated small-diameter rat sensory neurons in primary culture. In vivo, behavioral effects of TRPVI and GRO/KC were examined by paw injections. Results Neurons isolated from lumbar DRGs 3 days after local inflammation showed enhanced TRPV1 function： tachyphylaxis （the decline in response to repeated applications of capsaicin） was significantly reduced. A similar effect on tachyphylaxis was observed in neurons pre-treated for 4 h in vitro with GRO/KC. This effect was blocked by H-89, a protein kinase A inhibitor. Consistent with the in vitro results, in vivo behavioral responses to paw injection of capsaicin were enhanced and prolonged by pre-injecting the paw with GRO/KC 4 h before the capsaicin injection. GRO/KC paw injections alone did not elicit pain behaviors. Conclusion Function of the TRPV1 channel is enhanced by DRG inflammation and these effects are preserved in vitro during short-term culture. The effects （decreased tachyphylaxis） are mimicked by incubation with GRO/KC, which has previously been found to be strongly upregulated in this and other pain models.展开更多
基金supported in part by National Institutes of Health Grants NS045594,NS055860,and AR068989 to J.M.Z.
文摘Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models： ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion （DRG）, which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability （but not spontaneous activity） measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.
基金supported by the grants from NIH/NINDS, USA (NS045594 and NS055860)
文摘Objective Inflammation at the level of the sensory dorsal root ganglia （DRGs） leads to robust mechanical pain behavior and the local inflammation has direct excitatory effects on sensory neurons including small, primarily no- ciceptive, neurons. These neurons express the transient receptor potential vanilloid-1 （TRPV1） channel, which integrates multiple signals of pain and inflammation. The aim of this study was to characterize the regulation of the TRPV1 channel by local DR（] inflammation and by growth-related oncogene （（]RO/KC, systemic name： CXCL1）, a cytokine known to be upregulated in inflamed DRGs. Methods Activation of the TRPV1 receptor with capsaicin was studied with patch clamp methods in acutely isolated small-diameter rat sensory neurons in primary culture. In vivo, behavioral effects of TRPVI and GRO/KC were examined by paw injections. Results Neurons isolated from lumbar DRGs 3 days after local inflammation showed enhanced TRPV1 function： tachyphylaxis （the decline in response to repeated applications of capsaicin） was significantly reduced. A similar effect on tachyphylaxis was observed in neurons pre-treated for 4 h in vitro with GRO/KC. This effect was blocked by H-89, a protein kinase A inhibitor. Consistent with the in vitro results, in vivo behavioral responses to paw injection of capsaicin were enhanced and prolonged by pre-injecting the paw with GRO/KC 4 h before the capsaicin injection. GRO/KC paw injections alone did not elicit pain behaviors. Conclusion Function of the TRPV1 channel is enhanced by DRG inflammation and these effects are preserved in vitro during short-term culture. The effects （decreased tachyphylaxis） are mimicked by incubation with GRO/KC, which has previously been found to be strongly upregulated in this and other pain models.
