chronic-post-ischemia-pain-model-for-complex-regional-pain-syndrome

Chronic Post-Ischemia Pain Model for Complex Regional Pain Syndrome Type-I in Rats

Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical ...

Key Laboratory of Acupuncture and Neurology of Zhejiang Province

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that has been widely known as a pain mediator involved in various pain states. Evidence indicates that ET-1 sensitizes transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in vivo. But the molecular mechanisms still remain unknown. We aim to explore whether ET-1 sensitizes TRPA1 in primary sensory neurons and the molecular mechanisms. Ca imaging, immunostaining, electrophysiology, animal behavioral assay combined with pharmacological experiments were performed. ET-1 sensitized TRPA1-mediated Ca responses in human embryonic kidney (HEK)293 cells as well as in cultured native mouse dorsal root ganglion (DRG) neurons. ET-1 also sensitized TRPA1 channel currents. ET-1 sensitized TRPA1 activated by endogenous agonist HO. ET receptor (ETR) colocalized with TRPA1 in DRG neurons. ET-1-induced TRPA1 sensitization in vivo was mediated via ETR and protein kinase A (PKA) pathway in HEK293 cells and DRG neurons. Pharmacological blocking of ETR, PKA, and TRPA1 significantly attenuated ET-1-induced mechanical hyperalgesia in mice. Our results suggest that TRPA1 acts as a molecular target for ET-1, and sensitization of TRPA1 through ETR-PKA pathway contributes to ET-1-induced mechanical hyperalgesia. Pharmacological targeting of TRPA1 and ETR-PKA pathway may provide effective strategies to alleviate pain conditions associated with ET-1.

ETR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia.

 Complex regional pain syndrome type-I (CRPS-I) is a progressive and devastating pain condition, which remains clinically challenging. The mechanisms of CRPS-I still remain largely unknown. We aim to identify transcriptome profiles of genes relevant to pain mechanisms and major pathways involved in CRPS-I.  A rat model of chronic post-ischemia pain (CPIP) was established to mimic CRPS-I. RNA-sequencing (RNA-Seq) was used to profile transcriptome of L4-6 dorsal root ganglia (DRGs) of a rat model of CRPS-I.  CPIP model rats developed persistent mechanical/thermal hyperalgesia in ipsilateral hind paw. RNA-Seq identified a total of 295 differentially expressed genes (DEGs), including 195 up- and 100 downregulated, in ipsilateral DRGs of CPIP rats compared with sham rats. The expression of several representative genes was confirmed by qPCR. Functional analysis of DEGs revealed that the most significant enriched biological processes of upregulated genes include response to lipopolysaccharide, inflammatory response and cytokine activity, which are all important mechanisms mediating pain. We further screened DEGs implicated in pain progress, genes enriched in small- to medium-sized sensory neurons and enriched in TRPV1-lineage nociceptors. By comparing our dataset with other published datasets of neuropathic or inflammatory pain models, we identified a core set of genes and pathways that extensively participate in CPIP and other neuropathic pain states.  Our study identified transcriptome gene changes in DRGs of an animal model of CRPS-I and could provide insights into identifying promising genes or pathways that can be potentially targeted to ameliorate CRPS-I.

Transcriptome profiling of dorsal root ganglia in a rat model of complex regional pain syndrome type-I reveals potential mechanisms involved in pain.

Paclitaxel-induced peripheral neuropathy is a common adverse effect during paclitaxel treatment resulting in sensory abnormalities and neuropathic pain during chemotherapy and in cancer survivors. Conventional therapies are usually ineffective and possess adverse effects. Here, we examined the effects of electroacupuncture (EA) on a rat model of paclitaxel-induced neuropathic pain and related mechanisms. EA robustly and persistently alleviated paclitaxel-induced pain hypersensitivities. Mechanistically, TLR4 (Toll-Like Receptor 4) and downstream signaling MyD88 (Myeloid Differentiation Primary Response 88) and TRPV1 (Transient Receptor Potential Vallinoid 1) were upregulated in dorsal root ganglion (DRGs) of paclitaxel-treated rats, whereas EA reduced their overexpression. Ca imaging further indicated that TRPV1 channel activity was enhanced in DRG neurons of paclitaxel-treated rats whereas EA suppressed the enhanced TRPV1 channel activity. Pharmacological blocking of TRPV1 mimics the analgesic effects of EA on the pain hypersensitivities, whereas capsaicin reversed EA's effect. Spinal astrocytes and microglia were activated in paclitaxel-treated rats, whereas EA reduced the activation. These results demonstrated that EA alleviates paclitaxel-induced peripheral neuropathic pain via mechanisms possibly involving suppressing TLR4 signaling and TRPV1 upregulation in DRG neurons, which further result in reduced spinal glia activation. Our work supports EA as a potential alternative therapy for paclitaxel-induced neuropathic pain.

Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons.

Gout arthritis, which is provoked by monosodium urate (MSU) crystal accumulation in the joint and periarticular tissues, induces severe pain and affects life quality of the patients. Eucalyptol (1, 8-cineol), the principal component in the essential oils of eucalyptus leaves, has been known to possess anti-inflammatory and analgesic properties. We aimed to examine the therapeutic effects of eucalyptol on gout arthritis and related mechanisms.

Article	Year
ETR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia. Molecular pain\| PubMed ID: 30990108	2019
Transcriptome profiling of dorsal root ganglia in a rat model of complex regional pain syndrome type-I reveals potential mechanisms involved in pain. Journal of pain research\| PubMed ID: 31114302	2019
Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons. International journal of molecular sciences\| PubMed ID: 31775332	2019
Eucalyptol Alleviates Inflammation and Pain Responses in a Mouse Model of Gout Arthritis. British journal of pharmacology\| PubMed ID: 31883118	2019

Xiaoli Zheng

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