title: Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures.
abstract: Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach in seizure disorders and to examine the differential mechanisms involved in opioid anti- (morphine at 0.5-3 mg/kg) versus pro-convulsant (20-100 mg/kg) effects. Systemic administration of ultra-low doses of naltrexone (100 fg/kg-10 ng/kg) significantly potentiated the anticonvulsant effect of morphine at 0.5 mg/kg while higher degrees of opioid receptor antagonism blocked this effect. Moreover, inhibition of opioid-induced excitatory signaling by naltrexone (1 ng/kg) unmasked a strong anticonvulsant effect for very low doses of morphine (1 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of opioid receptor signaling can exert strong seizure-protective effects even at very low levels of opioid receptor activation. However, ultra-low dose naltrexone could not increase the maximal anticonvulsant effect of morphine (1-3 mg/kg), possibly due to a ceiling effect. The proconvulsant effects of morphine on seizure threshold were minimally altered by ultra-low doses of naltrexone while being completely blocked by a higher dose (1 mg/kg) of the antagonist. The present data suggest that ultra-low doses of opioid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of opioids.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Honar
authors.forename: K
authors.initials: K
authors.lastname: Riazi
authors.forename: H
authors.initials: H
authors.lastname: Homayoun
authors.forename: H
authors.initials: H
authors.lastname: Sadeghipour
authors.forename: N
authors.initials: N
authors.lastname: Rashidi
authors.forename: M R
authors.initials: MR
authors.lastname: Ebrahimkhani
authors.forename: N
authors.initials: N
authors.lastname: Mirazi
authors.forename: A R
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D004056:Differential Threshold / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D051379:Mice; D009020:Morphine / Q000627:therapeutic use*; D009271:Naltrexone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009294:Narcotics / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D009271:Naltrexone; D009020:Morphine; D010433:Pentylenetetrazole