Consequences of receptor cross talk on inflammation and algesia

我们发现，存在于背根神经节(DRG)的神经元，类似于白细胞，表达多种细胞因子、趋化因子、阿片类物质、去雄激素和其他神经肽的受体。我们以前曾证明，预先暴露于趋化因子如MIP1-α会导致PKC介导的阿片受体对阿片类药物的趋化反应脱敏，从而潜在地增强疼痛。在阿片类药物进入中枢PAG之前，给予MIP-α或RANTES大鼠的增强甩尾实验表明，阿片类药物的镇痛作用明显减弱。然后，我们扩展了这些早期的研究，表明预先给予趋化因子敏化和启动辣椒素或花椒胺刺激的香草素(TRPV1)痛觉受体在DRG神经元上的钙流。这种反应也增加了疼痛，表现为在体内鞘内注射辣椒素之前给予趋化因子后，爪子缩回的增强。香草素受体的这种敏化也依赖于PKC。因此，促炎趋化因子可以通过抑制阿片类药物和增强香草素受体反应来增加疼痛。我们目前的项目专注于神经免疫相互作用对癌症患者痛感的影响，此前由NIAID和NCI提供的INIP博士后IRA资金资助。如前所述，趋化因子受体串扰抑制了止痛阿片受体，但增强了痛性瞬时受体电位通道(TRP)受体，从而导致疼痛的炎症。A)NIAID与Jeffrey Cohen博士合作，在化疗诱发带状疱疹的棉鼠疱疹病毒感染模型中进行了研究。疱疹病毒感染背根神经节会导致神经束上极其痛苦的炎症反应。有报道称，VZV感染可产生TLR配体，我们发现存在于背根神经节的外周神经元表达TLR3、7和9，当受到刺激时，TLR3、7和9表达许多细胞因子和趋化因子的mRNA。此外，TLR配体对神经元的刺激可上调TLRs的表达并反式激活TRPV1。此外，将神经元与TLR配体预先孵育16小时，可增强辣椒素刺激TRPV1所诱导的钙离子通量。因此，疱疹病毒与这些TLR相互作用的产物可以直接或间接地通过诱导趋化因子，增强TRPV1疼痛受体的反应，为免疫抑制的癌症患者带状疱疹神经痛提供了可能的基础。此外，在小鼠肿瘤模型中，发现给予阻断TLR9的抑制性寡核苷酸可以抑制对热的敏感性增强，这被认为是由TRPV1介导的。这为免疫和痛觉感受器之间的串扰提供了额外的证据。这些在疼痛模型中的研究表明，许多癌症患者报告的外周疼痛可以通过有效调节神经免疫分子来解决。

We established that neurons present in dorsal root ganglia (DRG), similar to leukocytes, express a wide variety of receptors for cytokines, chemokines, opioids, anandamide and other neuropeptides. We previously showed that prior exposure to chemokines such as MIP1-alpha results in PKC mediated desensitization of the chemotactic response to opioids by opioid receptors, and thus potentially enhances pain. This decrease in the analgesic effect of opioids was evident from the enhanced tail flick assay of rats administered MIP-alpha or RANTES prior to an analgesic opioid into the PAG of the CNS. We then extended these earlier studies by showing that prior administration of chemokines sensitized and primed the calcium flux of capsaicin or anandamide stimulated vanilloid (TRPV1) algesic receptor on DRG neurons. This response also increased pain as shown by the enhancement of paw withdrawal in response to the intrathecal administration of the chemokine prior to capsaicin in vivo. This sensitization of the vanilloid receptor was also PKC dependent. Consequently, proinflammatory chemokines can increase pain both by suppressing opioid and enhancing vanilloid receptor responses. Our current project focuses on neuroimmune interactions contributing to pain sensation in cancer patients previously funded by an INIP postdoctoral IRA financial grant from NIAID and NCI. As previously shown, chemokine receptor cross-talk suppresses analgesic opioid receptors, but enhances algesic transient receptor potential channel (TRP) receptors, thus resulting in painful inflammation. a) In collaboration with Dr. Jeffrey Cohen, NIAID we have investigated this in a cotton rat herpes virus infection model for chemotherapy induced Herpes Zoster. Herpes infection of dorsal root ganglia results in extremely painful inflammatory responses along nerve tracts. It has been reported that VZV infection produces TLR ligands and we have found that peripheral neurons present in dorsal root ganglia express TLR3, 7 and 9 which when stimulated express mRNA for many cytokines and chemokines. In addition, TLR ligand stimulation of neurons upregulate the expression of TLRs and transactivate TRPV1. Furthermore, preincubation of neurons for 16 hours with the TLR ligands, enhances the calcium flux induced by capsaicin stimulation of TRPV1. Consequently, products of the herpes virus interacting with these TLR's can either directly or indirectly, by inducing chemokines, enhance the response of TRPV1 pain receptors, providing one possible basis for herpes Zoster neuralgesia in immunosuppressed cancer patients. Furthermore, in a mouse tumor model administration of suppressive oligonucleotides that block TLR9 were found to inhibit enhanced sensitivity to heat, which is considered to be mediated by TRPV1. This provides additional evidence for the cross-talk between immune and pain sensing receptors. These studies in a pain model suggest that the peripheral pain reported by many cancer patients may be addressed by effective regulation of neuroimmune molecules.