A Novel Morphine Drinking Model of Opioid Dependence in Rats

Abstract

An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

New perspective for an old drug: Can naloxone be considered an antioxidant agent?

“…NLX is an antagonist of the opioid receptors, widely expressed on cells of the central and peripheral nervous systems [ 28 , 29 ]. Polyphenols are the largest family of antioxidants.…”

Chronic morphine exposure and maternal separation induce impairments in cognition and locomotor activity of male adolescent rats

“…It has been shown that MS for 240 min/day from PND 1 to 21 enhances the locomotor activity of rats of all ages, but MS for 180 min/day from PND 1 to 21 does not affect locomotor activity in male adolescent rats (Wang et al, 2015). Morphine consumption has previously been linked to significant hyperlocomotion (Berríos-C arcamo et al, 2022). In the present study, MS intervention led to the greater total distance moved and mean velocities in the OF test as indicators of locomotor activity, while chronic maternal morphine exposure had no effect; therefore, this result is not in agreement with the latter.…”

Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats

“…Some research has claimed that the aversive properties of abused drugs could be used for anti-addiction approaches by developing them to block or interfere with rewarding properties ( He et al, 2019 ; Yu et al, 2021 ; Riley et al, 2022 ). A similar concept was previously employed for alcohol and nicotine addiction ( Mann, 2004 ; Casarrubea et al, 2015 ; Berrios-Carcamo et al, 2022 ). For example, the anti-alcohol consumption drug disulfiram disinhibited acetaldehyde hydrogenase.…”

“…This caused higher amounts of acetaldehyde levels in the plasma, resulting in flushing, nausea, headache, and increases in heart rate aimed at deterring alcohol consumption ( Mann, 2004 ). Morphine drinking produced an aversively bitter taste, enhancing avoidance behavior and counteracting the rewarding property of morphine-induced approaching behaviors ( Berrios-Carcamo et al, 2022 ). Acute nicotine administrations elicited aversive anxiety behaviors to decrease the probability of nicotine addiction ( Casarrubea et al, 2015 ).…”