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.

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia

“…NaV1.9, a tetrodotoxin (TTX) resistant sodium channel is involved in cold sensation, 58 and TTX resistant channels, including NaV1.9, are upregulated by morphine or morphine’s metabolite M3G. 11, 27 The response of the TRPM8 channel, however, would not depend on the presence of NaV1.9, since the NaV1.9 KO mice still respond to TRPM8/TRPA1 blockers. 58 Finally, we can speculate that a downregulation of the TASK-3 leak potassium channel in a subpopulation of TRPM8 neurons 64 might also be involved in the increased cold sensitivity in morphine treated rats.…”

Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway

“…Nassirpour's work showed that primary hippocampal neuron culture incubated with 100 lM morphine for 20 h exhibited significant inhibition on excitatory and inhibitory synaptic transmission, which was mediated by the activation of G-protein-activated inwardly rectifying potassium channel (GIRK) (Nassirpour et al, 2010). It's well recognized that adaptive change theories, including synaptic transmission and alterations in neuronal excitability after chronic morphine treatments are another facet of the mechanisms underlying the development of tolerance (Chen et al, 2012a;Mao et al, 2002a;Zhao and Joo, 2006). Most importantly, based on this culture model, significant elevations in Akt phosphorylation and increased IL-1b release resulting from enhanced Caspase-1 maturation and NALP1 inflammasome activation after morphine incubation were observed.…”

Rapid tolerance to morphine in the myenteric neurons of the small intestine is independent of β-arrestin-2 and mediated by PKC

“…Voltage-gated sodium channels are critical to the action potential upstroke and altered sodiumchannel kinetics in acute and chronic morphine-treated DRG and myenteric neurons have been demonstrated previously (Chen et al, 2012;Smith et al, 2012Smith et al, , 2014Mischel et al, 2018). Analysis of single-cell RNA sequencing data from Zeisel at al.…”