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Time dependent gene expression post SNL in IPSA vs Contralateral DRGs

ABSTRACT: Chronic pain can be debilitating, and current treatments are neither universally efficacious, nor without risks. New therapeutic options are needed. Transient receptor potential (TRP) ion channels regulate inflammation and pain. Understanding how endogenous TRP ligands regulate inflammation and pain may provide insights for new therapies. Spinal nerve ligation (SNL) injury was used as a model for chronic pain. Transcriptomic and targeted lipidomic analysis of damaged tissue revealed time-dependent increases in Cyp1b1 mRNA and a concurrent accumulation of 8,9-EET and 19,20-EpDPA post injury. Production of 8,9-EET and 19,20-EpDPA by human CYP1B1 and mouse Cyp1b1 was confirmed in vitro. 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptigergic DRG neurons. Activation of TRPA1 was attenuated by the antagonist A967079, and mouse Trpa1 was more responsive to agonists including 8,9-EET and 19,20-EpDPA than human TRPA1. This latter effect was mediated in part by amino acids Y933, G939, and S921. Intra-plantar injection of 19,20-EpDPA induced acute mechanical, but not thermal hypersensitivity in mice, which was blocked by A967079. Similarly, Cyp1b1 knockout mice displayed a reduced chronic pain phenotype, indicating a role for Cyp1b1-derived oxylipins in promoting Trpa1 activation and pain. Manipulation of the CYP1B1-oxylipin-TRPA1 axis following nerve injury could have therapeutic benefit.

ORGANISM(S): Mus musculus

PROVIDER: GSE194174 | GEO | 2023/02/01

REPOSITORIES: GEO

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Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].

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Time dependent gene expression post SNL in IPSA vs Contralateral DRGs

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