Electrical Synapses: High-speed Communication in the Maintenance of Neuropathic Pain.

Anesthesiology, V 124 • No 1 13 January 2016 I this issue of A Nesthesiology, Chen et al.1 evaluated the role of a neuronally expressed electrical synapse (also called a gap junction) in neuropathic pain in rats. electrical synapses are not well known to anesthesiologists or pain physicians although they were first described in the early 1900s by golgi.2 An electrical synapse is formed by gap junctions between two neurons that directly abut each other with a distance of approximately 3 nm. The 1906 Nobel Prize for Physiology and Medicine was jointly awarded to golgi, a proponent of the electrical synapse, and santiago Ramon y Cajal, who described the more familiar chemical synapse. This prize was controversial as the two ideas were then thought to be mutually exclusive. in retrospect, the choice of the Nobel Committee was prescient as now it appears that not only do both methods of signaling exist, but they also interact importantly. electrical synapses provide a fast and simple signaling mechanism through specialized junctions that allow for bidirectional ionic current flow (fig. 1). electrical synapses are formed by two hemichannels on opposing cells, each of which is made up of six connexin protein subunits. There are multiple connexin isoforms in humans and mice, which are named for their predicted molecular weights, for example, Cx36 studied by Chen et al.1 has a mass of approximately 36 kDa. interestingly, specific central nervous system cell types differentially express connexin protein isoforms. For example, astrocytes highly express Cx43, whereas neurons highly express Cx36. Chen et al.1 evaluated the role of electrical channels composed of Cx36 in the anterior cingulate cortex (ACC) of mice using the chronic constriction injury model of neuropathic pain. Functional magnetic resonance imaging studies show an enhanced neuronal activity in the ACC in anticipation of painful stimuli and in chronic pain conditions, and surgical lesioning of the ACC alters the affective response to noxious stimuli but not the ability to localize it. This suggests that the anterior cingulate is an area of association cortex that is important to the interaction between the affective and primary nociceptive response to injury. interestingly, Chen et al.1 only saw an up-regulation of Cx36 in the ACC consistent with hyperalgesia after chronic constriction injury, not in other brain areas evaluated. They then went on to use short-hairpin RNA against Cx36 delivered directly to the ACC by implanted cannula to block its expression and found that they could reverse mechanical allodynia and thermal hyperalgesia after nerve injury. given the known role of the ACC in the affective component of pain, it would have been interesting to evaluate the behaviors (such as conditioned place avoidance) after the above manipulations to more determine whether the change in nociception was actually secondary to a change in the perceived unpleasantness of the stimuli. An important translational step was the use of systemically administered gap junction blockers, which were also shown to reverse the pain behaviors without affecting motor function. one of these gap junction blockers, mefloquine, a quinine derivative, is selective for Cx36 and is already routinely given to patients for the prevention and treatment of malaria. in contrast to electrical synapses, the classic chemical synapse consists of a presynaptic neuron that releases neurotransmitters from synaptic vesicles that cross a wider Electrical Synapses