GABAergic influence on temporomandibular joint-responsive spinomedullary neurons depends on estrogen status

Neuroscience. 2014 Feb 14;259:53-62. doi: 10.1016/j.neuroscience.2013.11.053. Epub 2013 Dec 4.


Sensory input from the temporomandibular joint (TMJ) to neurons in superficial laminae at the spinomedullary (Vc/C1-2) region is strongly influenced by estrogen status. This study determined if GABAergic mechanisms play a role in estrogen modulation of TMJ nociceptive processing in ovariectomized female rats treated with high- (HE) or low-dose (LE) estradiol (E2) for 2days. Superficial laminae neurons were activated by ATP (1mM) injections into the joint space. The selective GABAA receptor antagonist, bicuculline methiodide (BMI, 5 or 50μM, 30μl), applied at the site of recording greatly enhanced the magnitude and duration of ATP-evoked responses in LE rats, but not in units from HE rats. The convergent cutaneous receptive field (RF) area of TMJ neurons was enlarged after BMI in LE but not HE rats, while resting discharge rates were increased after BMI independent of estrogen status. By contrast, the selective GABAA receptor agonist, muscimol (50μM, 30μl), significantly reduced the magnitude and duration of ATP-evoked activity, resting discharge rate, and cutaneous RF area of TMJ neurons in LE and HE rats, whereas lower doses (5μM) affected only units from LE rats. Protein levels of GABAA receptor β3 isoform at the Vc/C1-2 region were similar for HE and LE rats. These results suggest that GABAergic mechanisms contribute significantly to background discharge rates and TMJ-evoked input to superficial laminae neurons at the Vc/C1-2 region. Estrogen status may gate the magnitude of GABAergic influence on TMJ neurons at the earliest stages of nociceptive processing at the spinomedullary region.

Keywords: ANOVA; AP5; Artificial Cerebrospinal fluid; BMI; D-(-)-2-amino-5-phosphonopentanoic acid; E2; EDTA; EGTA; ER; GABAA receptor; HE; LE; N-methyl-d-aspartate; NMDA; NMDA receptor subtype; NR2B; OvX; PAG; PBS; RF; RVM; Rmag; SA; SD; SG; TG; TMJ; TMJD; aCSF; analysis of variance; bicuculline methiodide; estradiol; estrogen receptor; ethylene glycol tetraacetic acid; ethylenediaminetetraacetic acid; high-dose estradiol; low-dose estradiol; nociception; ovariectomized; periaqueductal gray; phosphate-buffered saline; receptive field; response magnitude; rostral ventromedial medulla; sex steroids; spontaneous activity; standard deviation; substantia gelatinosa; temporomandibular joint; temporomandibular joint/muscle disorders; trigeminal brainstem; trigeminal ganglion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Dose-Response Relationship, Drug
  • Estrogens / metabolism*
  • Female
  • GABA Agents / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Ovariectomy
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Receptors, GABA-A / metabolism*
  • Temporomandibular Joint / cytology*
  • Trigeminal Caudal Nucleus / cytology*


  • Estrogens
  • GABA Agents
  • Receptors, GABA-A
  • Adenosine Triphosphate