Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation

Morphine is one of the most commonly used drugs for the treatment of severe pain. It is derived from opium, which is extracted from poppies, and binds to the same receptors in the brain as the body's own naturally produced painkillers. As well as providing pain relief, morphine can act directly on the brain's reward system to trigger a state of euphoria, and can therefore be highly addictive. One of the key components of the brain's reward circuit that morphine affects is called the ventral tegmental area (VTA). The activity of the VTA is regulated by the combined efforts of two groups of cells: excitatory glutamatergic neurons that increase VTA activity and inhibitory interneuronsthat reduce the activity of the VTA. Morphine inhibits the interneurons, thereby allowing the glutamatergic neurons to activate the VTA. But does morphine also strengthen this excitatory input directly? By examining the effects of morphine on individual VTA neurons, Chen et al. show that the drug does indeed enhance the activity of the glutamatergic neurons. However, it does so indirectly by inhibiting another group of interneurons that would otherwise silence the glutamatergic neurons. This effect of morphine is dependent on the drug acting on a specific receptor type on the interneurons. Chen et al. show that injecting a drug that blocks these receptors straight into the VTA of rats prevents morphine from increasing the animals' activity levels. It also prevents the animals from developing a preference for being in locations where they have previously received morphine. This suggests that morphine could primarily exert its pleasurable effects by preventing the glutamatergic neurons from being inhibited, and thus allowing them to activate the VTA neurons.