Topical Application of Loperamide/Oxymorphindole, Mu and Delta Opioid Receptor Agonists, Reduces Sensitization of C-fiber Nociceptors that Possess NaV1.8

Megan L. Uhelski; Daniel Bruce; Rebecca Speltz; George L. Wilcox; Donald A. Simone

doi:10.1016/j.neuroscience.2020.08.022

Topical Application of Loperamide/Oxymorphindole, Mu and Delta Opioid Receptor Agonists, Reduces Sensitization of C-fiber Nociceptors that Possess Na_V1.8

Megan L. Uhelski, Daniel Bruce, Rebecca Speltz, George L. Wilcox, Donald A. Simone

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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 Na_V1.8 voltage-gated sodium channels. These mice (Na_V1.8-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 Na_V1.8 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)
Pages (from-to)	102-112
Number of pages	11
Journal	Neuroscience
Volume	446
DOIs	https://doi.org/10.1016/j.neuroscience.2020.08.022
State	Published - Oct 15 2020

Bibliographical note

Funding 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).

Funding Information:
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.

Publisher Copyright:
© 2020 IBRO

Keywords

antinocicepton
electrophysiology
hyperalgesia
nociceptor sensitization
opioids

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10.1016/j.neuroscience.2020.08.022

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@article{7f9feffa01204b5983b0ef26cf3cb608,

title = "Topical Application of Loperamide/Oxymorphindole, Mu and Delta Opioid Receptor Agonists, Reduces Sensitization of C-fiber Nociceptors that Possess NaV1.8",

abstract = "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 na{\"i}ve 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 na{\"i}ve 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.",

keywords = "antinocicepton, electrophysiology, hyperalgesia, nociceptor sensitization, opioids",

author = "Uhelski, {Megan L.} and Daniel Bruce and Rebecca Speltz and Wilcox, {George L.} and Simone, {Donald A.}",

note = "Funding Information: The authors extend their thanks to Dr. Philippe S{\'e}guela 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 Akg{\"u}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). Funding Information: 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. Publisher Copyright: {\textcopyright} 2020 IBRO",

year = "2020",

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day = "15",

doi = "10.1016/j.neuroscience.2020.08.022",

language = "English (US)",

volume = "446",

pages = "102--112",

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T1 - Topical Application of Loperamide/Oxymorphindole, Mu and Delta Opioid Receptor Agonists, Reduces Sensitization of C-fiber Nociceptors that Possess NaV1.8

AU - Uhelski, Megan L.

AU - Bruce, Daniel

AU - Speltz, Rebecca

AU - Wilcox, George L.

AU - Simone, Donald A.

N1 - Funding 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). Funding Information: 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. Publisher Copyright: © 2020 IBRO

PY - 2020/10/15

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N2 - 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.

AB - 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.

KW - antinocicepton

KW - electrophysiology

KW - hyperalgesia

KW - nociceptor sensitization

KW - opioids

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