Sex and estrus cycle differences in the modulatory effects of morphine on seizure susceptibility in mice.
OBJECTIVE
To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine.


METHODS
The threshold for the clonic seizures (CST) induced by acute intravenous administration of gamma-aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy.


RESULTS
At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5-3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine.


CONCLUSIONS
The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Kiarash
K
Riazi
Hooman
H
Honar
Houman
H
Homayoun
Narges
N
Rashidi
Mehdi
M
Dehghani
Hamed
H
Sadeghipour
Seyed Ali
SA
Gaskari
Ahmad Reza
AR
Dehpour
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D030762:Estrous Cycle / Q000502:physiology*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009919:Orchiectomy; D010052:Ovariectomy; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D012737:Sex Factors
D000927:Anticonvulsants; D003292:Convulsants; D012739:Gonadal Steroid Hormones; D009292:Narcotic Antagonists; D009271:Naltrexone; D009020:Morphine; D010433:Pentylenetetrazole