Treatment of pain with morphine leads to paradoxical hyperalgesia. The authors provide evidence that morphine-induced hyperalgesia is a result of downregulation of the chloride transporter KCC2 in spinal lamina I neurons. Microglial expression of P2X4 receptors and release of BDNF may underlie this change in neuronal chloride homeostasis and morphine-induced hyperalgesia. A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K+-Cl− co-transporter KCC2, impairing Cl− homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor–dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl− homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.

Microglia‐neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain‐derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB‐mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K ⁺ ‐Cl ⁻ cotransporter KCC2, dysrupting Cl ⁻ homeostasis, and hence the strength of GABA _A ‐ and glycine receptor‐mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions.

Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, is released in the bloodstream in response to a negative energetic status. Since discovery, the hypothalamus was identified as the main source of ghrelin in the CNS, and effects of the peptide have been mainly observed in this area of the brain. In recent years, an increasing number of studies have reported ghrelin synthesis and effects in specific populations of neurons also outside the hypothalamus. Thus, ghrelin activity has been described in midbrain, hindbrain, hippocampus, and spinal cord. The spectrum of functions and biological effects produced by the peptide on central neurons is remarkably wide and complex. It ranges from modulation of membrane excitability, to control of neurotransmitter release, neuronal gene expression, and neuronal survival and proliferation. There is not at present a general consensus concerning the source of ghrelin acting on central neurons. Whereas it is widely accepted that the hypothalamus represents the most important endogenous source of the hormone in CNS, the existence of extra-hypothalamic ghrelin-synthesizing neurons is still controversial. In addition, circulating ghrelin can theoretically be another natural ligand for central ghrelin receptors. This paper gives an overview on the distribution of ghrelin and its receptor across the CNS and critically analyses the data available so far as regarding the effects of ghrelin on central neurotransmission.