Consequences of receptor cross talk on inflammation and algesia

我们发现，与白细胞类似，存在于背根神经节（DRG）中的神经元表达多种细胞因子、趋化因子、阿片样物质、anandamide和其他神经肽的受体。我们之前的研究表明，先前暴露于趋化因子如MIP1-alpha会导致PKC介导的阿片受体对阿片的趋化反应脱敏，从而潜在地增强疼痛。阿片类药物镇痛作用的减弱从大鼠在将镇痛阿片类药物注入中枢神经系统PAG之前给予MIP-alpha或RANTES的尾部轻拍实验中可以明显看出。然后，我们扩展了这些早期的研究，表明事先给药的趋化因子使辣椒素或anandamide的钙通量增敏并启动，刺激了DRG神经元上的香草素（TRPV1）痛觉受体。这种反应也增加了疼痛，正如在体内使用辣椒素之前，在鞘内施用趋化因子时，脚爪退缩的增强所显示的那样。这种香草素受体的敏化也依赖于PKC。因此，促炎趋化因子可以通过抑制阿片样物质和增强香草样物质受体反应来增加疼痛。我们目前的项目重点是神经免疫相互作用对癌症患者疼痛感觉的影响，由NIAID和NCI资助的INIP博士后IRA财务资助。如前所述，趋化因子受体串话抑制镇痛类阿片受体，但增强痛觉瞬时受体电位通道（TRP）受体，从而导致疼痛性炎症。a)与NIAID的Jeffrey Cohen博士合作，我们在化疗诱导带状疱疹的棉花大鼠疱疹病毒感染模型中对此进行了研究。背根神经节疱疹感染导致沿神经束极度疼痛的炎症反应。据报道，VZV感染产生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，当刺激时表达许多细胞因子和趋化因子的mRNA。此外，TLR配体刺激神经元可上调TLR的表达，并使TRPV1反激活。此外，TLR配体对神经元进行16小时的预孵育，可以增强辣椒素刺激TRPV1诱导的钙通量。因此，疱疹病毒的产物与这些TLR的相互作用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，阻断TLR9的抑制性寡核苷酸被发现可以抑制对热的增强敏感性，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能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 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 indicate that the peripheral pain reported by many cancer patients may be addressed by effective regulation of neuroimmune molecules.