Activation of mu-opioid receptors slows pacemaking in hypothalamic A11 dopamine neurons

Abstract

Hypothalamic A11 dopamine neurons provide the only known source of spinal dopamine and critically modulate pain and motor systems. Yet, the electrophysiological properties of A11 neurons were unknown. Here, we characterized A11 dopamine neurons in mice using brain slice immunohistochemistry, and fluorescence-guided whole-cell patch-clamp and cell-attached electrophysiology. A11 dopamine neurons contained the enzymes necessary to synthesize dopamine, projected to the spinal cord, and were small, morphologically simple, and high resistance. Additionally, they received excitatory glutamatergic and inhibitory GABAergic synaptic input. Most A11 dopamine neurons fired action potentials spontaneously in a rhythmic pacemaker manner at [~]5 Hz, while the remainder were quiescent at rest, but fired readily with somatic current injection. Pacemaking A11 dopamine neurons were differentiated from quiescent neurons by a net inward current at subthreshold potentials. Activation of mu-opioid receptors reduced the net inward current at subthreshold potentials via activation of potassium current but also decreased GABAergic synaptic currents onto A11 dopamine neurons. Using cell-attached recording to preserve the natural chloride gradient, we found mu-opioid receptor agonism reduced spontaneous action potential firing of A11 dopamine neurons. The results lay the necessary framework for future studies investigating synaptic and ion channel mechanisms underlying the excitability in A11 dopamine neurons in physiological and pathological conditions.