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

Neurochem Res. 2015 Jun;40(6):1267-73. doi: 10.1007/s11064-015-1592-3. Epub 2015 May 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / administration & dosage
  • Amines / pharmacology
  • Analgesics / administration & dosage
  • Analgesics / pharmacology
  • Animals
  • Behavior, Animal
  • Calcium Channels / biosynthesis*
  • Calcium Channels, L-Type
  • Chronic Pain / drug therapy
  • Cyclohexanecarboxylic Acids / administration & dosage
  • Cyclohexanecarboxylic Acids / pharmacology
  • Endometriosis / complications
  • Endometriosis / physiopathology*
  • Endometriosis / psychology
  • Female
  • Gabapentin
  • Hyperalgesia / etiology
  • Hyperalgesia / physiopathology*
  • Hyperalgesia / psychology
  • Immunization
  • Injections, Spinal
  • Oligonucleotides, Antisense / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / metabolism*
  • Up-Regulation
  • gamma-Aminobutyric Acid / administration & dosage
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Amines
  • Analgesics
  • Cacna2d1 protein, rat
  • Calcium Channels
  • Calcium Channels, L-Type
  • Cyclohexanecarboxylic Acids
  • Oligonucleotides, Antisense
  • gamma-Aminobutyric Acid
  • Gabapentin