Central antitussive effect of codeine in the anesthetized rabbit
Eur J Med Res
c En t Ra L a n t It USSIVE EFFEc t o F c o d EIn E In t HE a n ESt HEt IZEd Ra BBIt
M. Simera 0
I. Poliacek 0
J. Jakus 0
0 Institute of Medical Biophysics, c omenius University , Martin , Slovakia
Backgr ound: c odeine represents a commonly used drug to suppress cough. c entral antitussive effect of codeine has been confirmed in a number of animal studies. However, available data related to antitussive activity of codeine in rabbits are very limited. Objective: We investigated the effects of codeine on cough, single expiratory responses (expiration-like reflex) induced by mechanical tracheo-bronchial stimulation, and on the sneeze reflex in the anesthetized rabbit. Material and methods: t wenty pentobarbitone anesthetized spontaneously breathing rabbits were used for the study. Increasing doses of codeine (codeinum dihydrogenphosphate, Interpharm) were injected intravenously (iv); 0, 0.15, 0.76, and 3.78 mg/kg of codeine dissolved in saline, 0.25 ml/kg) or intracerebroventricularly (icv); 0, 0.015, 0.076, and 0.378 mg/kg of codeine dissolved in artificial cerebrospinal fluid, 0.033 ml/kg. Results: Both iv and icv injections of codeine led to a dose-dependent reduction of coughing provoked by tracheo-bronchial stimulation; however, the doses differed substantially. t he effective cumulative dose for a 50% reduction in the number of coughs was 3.9 and 0.11 mg/kg after iv and icv administration of codeine, respectively; representing about 35-fold higher efficacy of the icv route. t he numbers of expiration-like responses and sneeze reflex responses remained unchanged. Conclusions: t he study confirmed the central antitussive effect of codeine, but showed a low sensitivity of sneeze and expiration reflex to codeine. We validated the experimental model of an anesthetized rabbit for studies on central antitussive action.
antitussive; tracheo-bronchial cough; sneeze; expiration; airway defense
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In t Ro d Uc t Io n
a ntitussive drugs, such as codeine and
dextromethorphan, are among the most commonly prescribed
medicines in the world. c odeine acts antitussively within
the brain stem, where the basic neuronal circuitry
responsible for coughing is located [
1-3
]. c entral action
of codeine is accepted, since the drug is more
effective when administered centrally, either via the
vertebral artery or intracerebroventricularly (icv) into the
4th brain ventricle, compared with an intravenous (iv)
route [
4
].
c odeine is considered to be primarily the µ-opioid
receptor agonist [
5, 6
]. However, for central
antitussives, including codeine, also other than µ-opioid
receptor mechanisms have been proposed [
5, 7-9
].
c odeine reduces the number of coughs provoked
by tracheo-bronchial stimulation; decreasing the
expiratory (E) component of cough efforts, with a much
lower effect on the inspiratory (I) one, cough timing,
and parameters of respiration [
10, 11
]. However, a
complete analysis of the effect of codeine on cough
motor pattern has never been performed in the rabbit
[12].
Previous studies have shown the effective
antitussive dose of codeine in experimentally produced
cough in anesthetized rabbits was 100 mg/kg for oral
and 1-10 mg/kg for iv administration [
13, 14
].
However, none of the studies have attempted to analyze and
determine Ed 50 (effective dose for 50% reduction of
coughing) providing the base for comparison of
antitussive efficacy upon different routes of codeine
administration and for the determination of its central
or peripheral action [
4, 11
].
In the present study we investigated the hypothesis
that in the rabbit the codeine would centrally suppress
tracheo-bronchial cough at a lower dose than that
required for iv administration.
Ma t ERIa L a n d MEt Ho d S
g En ERa L PRo c Ed URES a n d St IMULa t Io n
a ll procedures were performed in accordance with the
laws, rules, and regulations of Slovakian g overnment
and Ec ; the Ethics c ommittee of Jessenius Faculty of
Medicine in Martin approved the protocols.
Experiments were performed in 20 rabbits (n ew
Zeland white, line P91; 3.65 ±0.15 kg) of either sex,
pre-medicated with the diazepam (a paurin, KRKa ,
c roatia; 5 mg/kg, im) and anesthetized with sodium
pentobarbital (Biowet, Pulawy, Poland; 35 mg/kg, ip).
Supplementary anesthetic doses were administered
(13 mg/kg, iv) as needed. a tropine (Biotika; 0.15
mg/kg, iv) was given at the beginning of the
experiment to reduce secretions. t he trachea, femoral artery
and vein were canulated. t he animals were allowed to
breathe spontaneously a gas mixture of 30-60%
oxygen, balanced by nitrogen. a rterial blood pressure
(BP), end-tidal c o 2 concentration (Et c o 2),
respiratory rate (RR), and body temperature were monitored
continuously. Body temperature was maintained at
39.0 ±0.5°c . Periodically, the samples of arterial blood
were removed for blood gases and pH analysis.
Bipolar fine wire hook electrodes were placed in the
crural diaphragm (d Ia ) and bilate (...truncated)