Nat. Neurosci. 16, 183–192 (2013)

Credit: NATURE NEUROSCIENCE

Morphine is a major component of pain-treatment strategies, targeting μ-opioid receptors, but opiate use can lead to tolerance as well as hyperalgesia, a paradoxical sensitization to pain. In their current work, Ferrini et al. found maximal morphine-induced hyperalgesia (MIH) occurred within seven days of twice-daily dosing of morphine in rats. To understand the mechanism of MIH and to determine whether outputs from spinal lamina I neurons were at play, the authors tested whether the Cl− gradient in these neurons, which are the target for morphine's analgesic effect, was affected by morphine. Indeed, repeated or high-dose morphine inhibited Cl− extrusion (causing Cl− accumulation) in these neurons. Stabilizing the anion gradient reversed the hyperalgesia. Morphine treatment led to a decrease in expression of the main regulator of Cl− homeostasis in these neurons, the K+-Cl− cotransporter KCC2. Spinal microglial cells, which are thought to disrupt lamina I neuron Cl− homeostasis, were necessary and sufficient for MIH. Microglial P2X4 receptors were upregulated with repeated morphine treatment, which in turn resulted in release of the growth factor BDNF, and this was sufficient to induce MIH. Notably, mice with a deletion of BDNF did not show MIH. These results suggest that MIH is driven by upregulation of P2X4Rs in microglia, leading to BDNF release and ultimately downregulation of KCC2 and disruption of Cl− homeostasis in lamina I neurons.