Upregulation of α₂δ-1 Calcium Channel Subunit in the Spinal Cord Contributes to Pelvic Organ Cross-Sensitization in a Rat Model of Experimentally-Induced Endometriosis.
Pelvic organ cross-sensitization, also termed as viscero-visceral referred hyperalgesia, is a major contributor to painful endometriosis. Its underlying mechanism is poorly understood. Clinical and basic studies have shown that gabapentin, a drug that binds to the α2δ-1 subunit of voltage-dependent calcium channels (Cavα2δ-1), is effective in treating chronic visceral pain. Accordingly, we hypothesized that pelvic organ cross-sensitization in painful endometriosis is mediated by an upregulation of Cavα2δ-1 in the spinal cord. We examined if the dysregulation of spinal Cavα2δ-1 subunit may play an important role in the development of ectopic growths-to-colon cross-sensitization in a rat model of experimentally-induced endometriosis. Our findings suggest that there was an increased Cavα2δ-1 expression in the dorsal horn and an ectopic growths-to-colon cross-sensitization in female rats with established endometriosis. Intrathecal administration of gabapentin (300 μg) remarkably reduced the ectopic growths-to-colon cross-sensitization in rats with established endometriosis. Furthermore, intrathecal injection of Cavα2δ-1 antisense oligodeoxynucleotides reversed the ectopic growths-to-colon cross-sensitization and also normalized the upregulation of spinal Cavα2δ-1 expression in endometriosis rats. The current study suggests that the upregulation of Cavα2δ-1 in the spinal cord may contribute to pelvic organ cross-sensitization in painful endometriosis. Our study may provide a biological basis for selectively targeting this pathway to relieve viscero-visceral referred hyperalgesia in patients with painful endometriosis.
Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongtinan Road, Chaoyang District, Beijing, 100020, China, sincerewy@yahoo.com.
Yun
Y
Wang
Meijuan
M
Zhang
Fang
F
Xie
Xueyang
X
Li
Mengmeng
M
Bao
Ning
N
Yang
Rong
R
Shi
Zhenyuan
Z
Wang
Anshi
A
Wu
Yun
Y
Guan
Yun
Y
Yue
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D015220:Calcium Channels / Q000096:biosynthesis*; D020746:Calcium Channels, L-Type; D059350:Chronic Pain / Q000188:drug therapy; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D004715:Endometriosis / Q000150:complications / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D000077206:Gabapentin; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology* / Q000523:psychology; D007114:Immunization; D007278:Injections, Spinal; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology
D000588:Amines; D000700:Analgesics; C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids; D016376:Oligonucleotides, Antisense; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin