Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.17.209437v1?rss=1 Authors: Muchhala, K. H., Jacob, J. C., Alam, I., Hasan, S., Khan, A., Kang, M., Dewey, W. L., Akbarali, H. I. Abstract: The differential rates of opioid tolerances raise the question of discrete underlying mechanisms. While opioid tolerance is strongly linked to the development of dependence, there is a dissociation between the two phenomena in the gut as tolerance does not develop to chronic opioid-induced constipation, but diarrhea still manifests upon withdrawal. Here, we find that tolerance develops to inhibition of small intestinal motility after one day of morphine exposure, and is more rapid compared to spinally-mediated antinociception and constipation in chronic morphine-treated mice. This tolerance can be reversed by protein kinase C (PKC) inhibition but not by {beta}-arrestin-2 deletion. Similarly, morphine tolerance develops to inhibition of neuronal excitability in ileum myenteric neurons independently of {beta}-arrestin-2 and is attenuated by inhibiting PKC. These findings reveal a potential mechanism for differences in the rates of tolerances to opioids and implicate myenteric neurons of the ileum as the primary cause for opioid-induced withdrawal effects. Copy rights belong to original authors. Visit the link for more info