Neuroplastic alteration of TTX-resistant sodium channel with visceral pain and morphine-induced hyperalgesia

Abstract

The discovery of the tetrodotoxin-resistant (TTX-R) Na ⁺ channel in nociceptive neurons has provided a special target for analgesic intervention. In a previous study we found that both morphine tolerance and persistent visceral inflammation resulted in visceral hyperalgesia. It has also been suggested that hyperexcitability of sensory neurons due to altered TTX-R Na ⁺ channel properties and expression contributes to hyperalgesia; however, we do not know if some TTX-R Na ⁺ channel property changes can be triggered by visceral hyperalgesia and morphine tolerance, or whether there are similar molecular or channel mechanisms in both situations. To evaluate the effects of morphine tolerance and visceral inflammation on the channel, we investigated the dorsal root ganglia (DRG) neuronal change following these chronic treatments. Using whole-cell patch clamp recording, we recorded TTX-R Na ⁺ currents in isolated adult rat lumbar and sacral (L6−S2) DRG neurons from normal and pathologic rats with colon inflammatory pain or chronic morphine treatment. We found that the amplitudes of TTX-R Na ⁺ currents were significantly increased in small-diameter DRG neurons with either morphine tolerance or visceral inflammatory pain. Meanwhile, the result also showed that those treatments altered the kinetics properties of the electrical current (ie, the activating and inactivating speed of the channel was accelerated). Our current results suggested that in both models, visceral chronic inflammatory pain and morphine tolerance causes electrophysiological changes in voltage-gated Na channels due to the chronic administration of these medications. For the first time, the present investigation explored the adaptations of this channel, which may contribute to the hyperexcitability of primary afferent nerves and hyperalgesia during these pathologic conditions. The results also suggest that neurophysiologic mechanisms of morphine tolerance and visceral hyperalgesia are related at the TTX-R Na ⁺ channel.