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.