Role of Anoctamin-1 and Bestrophin-1 in Spinal Nerve Ligation-Induced Neuropathic Pain in Rats

Abstract

BackgroundCalcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors.ResultsL5/L6 spinal nerve ligation induced mechanical tactile allodynia. Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia. Intrathecal administration of selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) also dose-dependently diminished tactile allodynia and thermal hyperalgesia. Anoctamin-1 and bestrophin-1 mRNA and protein were expressed in the dorsal spinal cord and DRG of naïve, sham and neuropathic rats. L5/L6 spinal nerve ligation rose mRNA and protein expression of anoctamin-1, but not bestrophin-1, in the dorsal spinal cord and DRG from day 1 to day 14 after nerve ligation. In addition, repeated administration of CaCCs inhibitors (T16Ainh-A01, CaCCinh-A01 or NFA) or anti-anoctamin-1 antibody prevented spinal nerve ligation-induced rises in anoctamin-1 mRNA and protein expression. Following spinal nerve ligation, the compound action potential generation of putative C fibers increased while selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) attenuated such increase.ConclusionsThere is functional anoctamin-1 and bestrophin-1 expression in rats at sites related to nociceptive processing. Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia. As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.Electronic supplementary materialThe online version of this article (doi:10.1186/s12990-015-0042-1) contains supplementary material, which is available to authorized users.

Bestrophin 1 and retinal disease

“…mBest1 expression both in cortical neurons and astrocytes was also detected by RT-PCR and confirmed by gene silencing for mBest1 with mBest1-shRNA (Lee et al, 2010; Oh et al, 2012; Park et al, 2009). Murine Best1 mRNA and protein have also been reportedly expressed in the dorsal spinal cord and dorsal root ganglion (Al-Jumaily et al, 2007; Andre et al, 2003; Pineda-Farias et al, 2015). …”

“…Upregulation of Best1 expression and enhanced Ca 2+ -activated Cl − current in dorsal root ganglion neurons after peripheral nerve axotomy (Boudes et al, 2009) or spinal nerve ligation (Pineda-Farias et al, 2015) have suggested a function for Best1 in nociceptive processing. Another study reported that Best1 had a positive, supportive role in the regenerative process of mechanosensitive afferent fibers after peripheral nerve injury (Boudes and Scamps, 2012), suggesting a function for Bestrophin in the regeneration of injured sensory neurons as well as the maintenance of neuropathic pain.…”

Anion exchanger 3 in dorsal root ganglion contributes to nerve injury-induced chronic mechanical allodynia and thermal hyperalgesia

“…Previous studies indicate that activation of Ca 2+ ‐activated chloride channels leads to chloride efflux and depolarization . In support of this, it has been reported that Ca 2+ ‐activated chloride channels blockers or genetic ablation reduce nerve injury‐induced neuropathic pain . Thus, it is likely that the antiallodynic and antihyperalgesic effects of DIDS may result from inhibition of Ca 2+ ‐activated chloride channels as well as blockade of AE3.…”

“…To bypass this situation, we used a functional anti‐AE3 antibody as a more selective tool to target AE3. This strategy was based on previous studies using antibodies against nerve growth factor (NGF), Nav1.7 channels, CXCR4 and either anoctamin‐1 or bestrophin‐1 in in‐vivo studies . Interestingly, anti‐AE3 antibody post‐treatment reversed nerve injury‐induced mechanical allodynia and thermal hyperalgesia as well as AE3 expression upregulation.…”

Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways

“…Beyond respiratory disease, antagonists of TMEM16A have been proposed to have utility in treating a wide variety of other diseases including, pulmonary hypertension (Namkung et al 2010, Forrest et al 2012, Heinze et al 2014, secretory diarrhea (Thiagarajah, Donowitz, andVerkman 2015, Ousingsawat et al 2011), polycystic kidney disease (Buchholz et al 2014), pain (Cho et al 2012, Lee et al 2014, Pineda-Farias et al 2015 and cancer. TMEM16A has been implicated in numerous cancers, including head and neck, esophageal, gastric, colorectal, lung, breast, prostate, pancreatic and glioma (reviewed recently by ).…”