Mechanism of Endogenous Opioid Action Induced by LF TENS in Non-Anesthetized Subjects with Pupil Miosis.

<p>The locus coeruleus-noradrenergic system (LC) has been suggested to be a key structure in arousal, and its firing frequency tone has been correlated with wakefulness, vigilance, and sensory and pain perception. The size of the pupil correlates with the activity of LC, and light increases the frequency of firing. The action of the LC excites the excitation pathway that directly induces pupil constriction and excites inhibitory interneurons in the inhibitory pathway, exciting the inhibitor of the inhibitor; the net result is a reduction of inhibition and, indirectly, an agonist effect of the excitatory pathway of pupil constriction. Opioids act on the inhibitory pathway, and TENS has been suggested to be activated via the ventral lateral PAG and the opioid pathway. According to Valentino [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122826#pone.0122826.ref074" target="_blank">74</a>] and Curtis [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122826#pone.0122826.ref075" target="_blank">75</a>], opioids reduce the activation of the LC, and corticotropin-releasing hormone (CRH) increases the firing rate. It is possible that low-frequency sensory TENS inhibits LC inhibitory interneurons, increasing the tone of the pupillary constrictor of the LC. TMD patients could suffer from an impairment of the inhibitory pathway stemming from the ventral lateral PAG. Consequently, pupil constriction in response to light is not counterbalanced by inhibition (smaller pupil size under yellow-green light), and low-frequency sensory TENS is unable to further induce pupil constriction. Red, excitation pathway; black, inhibitory pathway.