Sex-dependent Cav2.3 channel contribution to the secondary hyperalgesia in a mice model of central sensitization

• Published in: Brain research 2021-08, Vol.1764, p.147438-147438, Article 147438
• Main Authors: Ferreira, Marcella Amorim, Lückemeyer, Débora Denardin, Macedo-Júnior, Sérgio José, Schran, Roberta Giusti, Silva, Ana Merian, Prudente, Arthur Silveira, Tonello, Raquel, Ferreira, Juliano
• Format: Article
• Language: English
• Subjects: Animals; Antisense oligonucleotide; Calcium channel; Calcium Channel Blockers - pharmacology; Calcium Channels, R-Type - drug effects; Calcium Channels, R-Type - genetics; Capsaicin; Cation Transport Proteins - drug effects; Cation Transport Proteins - genetics; Central Nervous System Sensitization - drug effects; Central Nervous System Sensitization - genetics; Central sensitization; Dose-Response Relationship, Drug; Female; Ganglia, Spinal - metabolism; Gene Knockdown Techniques; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - genetics; Male; Mice; Mice, Inbred C57BL; Oligonucleotides, Antisense - pharmacology; R-type; Sex Characteristics; Spider Venoms - pharmacology; Spinal Cord - metabolism
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2021.147438

Female and male mica were submitted to the secondary hyperalgesia induced by capsaicin. These animals were treated intrathecally with SNX-482, a pharmacological blocker of VGCC Cav2.3, and with an ASO against Cav2.3 for knockdown. After these treatments, female mice had an anti-hyperalgesic effect while male mice remained hyperalgesia. Cav2.3 inhibition or knockdown has antinociceptive effect in a sexually dimorphic way. Thanks for MindGraph for the figures used in this graphical abstract. [Display omitted] •SNX-482 reverses hyperalgesia just in female mice, but not induces adverse effects.•Cav2.3 knockdown produces antinociceptive effect just in female mice.•Cav2.3 inhibition or knockdown has antinociceptive effect in a sexually dimorphic way. Central sensitization (CS) is characteristic of difficult to treat painful conditions, such as fibromyalgia and neuropathies and have sexual dimorphism involved. The calcium influx in nociceptive neurons is a key trigger for CS and the role of Cav2.1 and Cav2.2 voltage gated calcium channels (VGCC) in this role were evidenced with the use of ω-agatoxin IVA and ω-agatoxin MVIIA blockers, respectively. However, the participation of the α1 subunit of the voltage-gated channel Cav2.3, which conducts R-type currents, in CS is unknown. Furthermore, the role of sexual differences in painful conditions is still poorly understood. Thus, we investigated the role of Cav2.3 in capsaicin-induced secondary hyperalgesia in mice, which serve as a CS model predictive of the efficacy of novel analgesic drugs. Capsaicin injection in C57BL/6 mice caused secondary hyperalgesia from one to five hours after injection, and the effects were similar in male and female mice. In female but not male mice, intrathecal treatment with the Cav2.3 inhibitor SNX-482 partially and briefly reversed secondary hyperalgesia at a dose (300 pmol/site) that did not cause adverse effects. Moreover, Cav2.3 expression in the dorsal root ganglia (DRG) and spinal cord was reduced by intrathecal treatment with an antisense oligonucleotide (ASO) targeting Cav2.3 in female and male mice. However, ASO treatment was able to provide a robust and durable prevention of secondary hyperalgesia caused by capsaicin in female mice, but not in male mice. Thus, our results demonstrate that Cav2.3 inhibition, especially in female mice, has a relevant impact on a model of CS. Our results provide a proof of concept for Cav2.3 as a molecular target. In addition, the result associat