It was recently shown that local injection, systemic administration or topical application of the peripherally-restricted mu-opioid receptor (MOR) agonist loperamide (Lo) and the delta-opioid receptor (DOR) agonist oxymorphindole (OMI) synergized to produce highly potent anti-hyperalgesia that was dependent on both MOR and DOR located in the periphery. We assessed peripheral mechanisms by which this Lo/OMI combination produces analgesia in mice expressing the light-sensitive protein channelrhodopsin2 (ChR2) in neurons that express NaV1.8 voltage-gated sodium channels. These mice (NaV1.8-ChR2+) enabled us to selectively target and record electrophysiological activity from these neurons (the majority of which are nociceptive) using blue light stimulation of the hind paw. We assessed the effect of Lo/OMI on nociceptor activity in both naïve mice and mice treated with complete Freund's adjuvant (CFA) to induce chronic inflammation of the hind paw. Teased fiber recording of tibial nerve fibers innervating the plantar hind paw revealed that the Lo/OMI combination reduced responses to light stimulation in naïve mice and attenuated spontaneous activity (SA) as well as responses to light and mechanical stimuli in CFA-treated mice. These results show that Lo/OMI reduces activity of C-fiber nociceptors that express NaV1.8 and corroborate recent behavioral studies demonstrating the potent analgesic effects of this drug combination. Because of its peripheral site of action, Lo/OMI might produce effective analgesia without the side effects associated with activation of opioid receptors in the central nervous system.
|Original language||English (US)|
|Number of pages||11|
|State||Published - Oct 15 2020|
Bibliographical noteFunding Information:
The authors extend their thanks to Dr. Philippe Séguela of McGill University for providing homozygous Na V 1.8-Cre mice to start the breeding colony for production of the Na V 1.8-ChR2 + mice. We also thank Drs. Phil Portoghese and Eyup Akgün for providing the OMI. This work was supported by NIH grant CA241627 to DAS, the R.W. Goltz Professorship in Dermatology (GLW), and the University of Minnesota Academic Health Center (GLW).
The authors extend their thanks to Dr. Philippe S?guela of McGill University for providing homozygous NaV1.8-Cre mice to start the breeding colony for production of the NaV1.8-ChR2+ mice. We also thank Drs. Phil Portoghese and Eyup Akg?n for providing the OMI. This work was supported by NIH grant CA241627 to DAS, the R.W. Goltz Professorship in Dermatology (GLW), and the University of Minnesota Academic Health Center (GLW). G.L.W. and D.B. are inventors on a University of Minesota international patent application. The remaining authors declare no competing financial interest.
© 2020 IBRO
- nociceptor sensitization