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Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

Background Dopaminergic neurons in the ventral tegmental area (VTA) of the brain are an important site of convergence of drugs and stress. We previously identified a form of long-term potentiation of GABAergic synapses on these neurons (LTPGABA). Our studies have shown that exposure to acute stress blocks this LTP, and that reversal of the block of LTPGABA is correlated with prevention of stress-induced reinstatement of cocaine-seeking. Methods Sprague-Dawley rats were subjected to cold-water swim stress. Midbrain slices were prepared following stress, and whole-cell patch clamp recordings of IPSCs were performed from VTA dopamine neurons. Antagonists of glucocorticoid and kappa opioid receptors were administered at varying time points after stress. Additionally, the ability of a post-stress kappa antagonist to block FSS-induced reinstatement of cocaine self-administration was tested. Results We report that an acute stressor blocks LTPGABA for five days after stress through a transient activation of glucocorticoid receptors and more lasting contribution of kappa opioid receptors. Pharmacological block of kappa opioid receptors beginning as late as 4 days after stress has occurred can reverse the block of LTPGABA. Furthermore, post-stress administration of a kappa opioid antagonist prevents reinstatement of cocaine-seeking. Conclusions Our results show that a brief stressor can cause days-long changes in the reward circuitry and reveal roles for glucocorticoid and kappa opioid receptors as mediators of the lasting effects of stress on synaptic plasticity. These results indicate that kappa opioid receptor antagonists reverse the neuroadaptations underlying stress-induced drug-seeking behavior and may be useful in the treatment of cocaine addiction.

Oxygen concentrators are a relatively new technology for the delivery of supplemental oxygen. Readily available for domicile use in modern countries, these machines have proved reliable. The application of oxygen concentrators for the supply of medical oxygen in remote high-altitude settings has important cost-saving and supply implications. In our experience at a remote hospital at 3,900 m in the Nepal Himalayas, oxygen concentrators constitute an effective and affordable means to supply medical oxygen. Using an air compressor and 2 zeolite chambers, the machine traps nitrogen from room air compressed to 4 atm, thus concentrating oxygen in the expressed gas. At delivery flow rates of 2 to 5 liters per minute, oxygen concentrations greater than 80% can be maintained. An electric power requirement of less than 400 W can be provided from a variety of sources, including a small gasoline generator, a solar or wind power system with battery store, or a domestic or commercial power source. At our facility, a cost savings of 75% for supplemental oxygen was found in favor of the oxygen concentrator over cylinders (0.17 US cents per liter vs 0.79 US cents per liter).

There is an absence of information in the literature regarding reascent to high altitude following resolution of HAPE (high altitude pulmonary edema). This report presents three cases of HAPE that are notable for later reascent to a high summit (up to 8,850 m) within the time course of each expedition. These cases illustrate that careful, gradual reascent following recovery and acclimatization after an episode of HAPE precipitated by rapid ascent may be considered. The pathophysiology of HAPE is reviewed with a focus on the evidence for rapid reversibility of pulmonary vascular injury. The evidence for protective pulmonary vascular remodeling is discussed to further support such a recommendation for cases of uncomplicated HAPE.

There is a clinical need for a safe and effective anesthetic technique in high altitude and remote areas. This report presents a series of 11 consecutive cases documenting the use of ketamine anesthesia in a remote hospital at an altitude of 3,900 m, by primary-care physicians without specialist training in anesthesia. The method of administration is fully described. At a low dose of 2.0 mg/kg, ketamine produces a dissociative anesthesia that does not depress the hypoxic drive, or interfere with the pharyngeal or laryngeal reflexes. Although supplemental oxygen is useful in the recovery phase for less acclimatized individuals, it is usually not required as reductions in oxygen saturation can be raised by physical stimulation that encourages the patient to breathe faster and deeper. The common side effect of emergent nightmares was avoided using midazolam as premedication and a quiet recovery area. This study offers the first available evidence that ketamine with midazolam offers a safe and effective means of anaesthesia at very high altitude, without the need for specialist equipment or training, by careful clinicians experienced in basic airway management.

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