Naloxone Antagonizes Soman‐induced Central Respiratory Depression in Rats

Abstract

The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.

Organophosphate Versus Opioid Poisoning

“…Naloxone has shown effectiveness in antagonizing soman (an OPC)-induced respiratory depression in rats by blocking endogenous opioid respiratory-control pathways that are independent of the stimulation of muscarinic receptors. These effects were also shown to be potentiated by coadministration of atropine 2 . Opioids induce respiratory depression via activation of μ-opioid receptors at the specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm–generating area in the pons.…”

“…These effects were also shown to be potentiated by coadministration of atropine. 2 Opioids induce respiratory depression via activation of μ-opioid receptors at the specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm-generating area in the pons. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone.…”

Preparing a rat brain tissue samples for acetylcholinesterase activity measurement: The MM method

“…respiratory muscle fatigue. 8,9 Knowing that, a crucial point in therapy would be reactivation of AChE in brain tissue. 15 Because of that, non-quaternary organic compounds are introduced as novel antidotes in OP poisoning.…”

“…5 Unlike the OPs, oximes generally have a low degree of penetration through the BBB, because of which they have little to no ability to reactivate brain AChE. 7 Knowing that central respiratory depression is a main cause of death in OP intoxication, 8,9 when researching a new oxime, it is very important to determine the degree of its penetration through the BBB. Finding an oxime that is more penetrable, would mean a greater therapeutic success.…”

Nerve agents: A clear and present danger to mankind

“…11 It is believed that even the central effects of nerve agents are consequence of the stimulation of muscarinic and nicotinic receptors in the brain, followed by the secondary stimulation of glutamatergic and opioidergic structures. 12 Poisoning with high doses of nerve agents brings Standard therapy is triple: administration of sufficiently high doses of atropine, AChE reactivators -oximes, such as pralidoxime salts (2-PAM or P2S), obidoxime (LüH-6) and asoxime (HI-6) and anticonvulsants, mainly diazepam or midazolam.14 Although atropine itself and especially when overdosed, exerts some adverse effects (tachycardia, xerostomia, impaired cognitive functions), it is essential to repeat the single shots of 2 mg each until the proper atropinisation is reached. It is a doctrinary position that mild atropine overdose is less dangerous than untreated anticholinestarese poisoning.…”