The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing
Copyright © 2021 International Association for the Study of Pain..
ABSTRACT: Activation of cannabinoid receptor type 1 (CB 1 ) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB 1 receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance, and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB 1 receptors to circumvent central CB 1 -related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB 1 -preferring agonist CB-13 on nociception and central CB 1 -related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB 1 -receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse dorsal root ganglion neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E 2 , providing potential mechanistic explanations for the analgesic actions of peripheral CB 1 receptor activation. With acute dosing, phenotypes associated with central CB 1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED 50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB 1 receptor dependence, even at a dose that did not produce central CB 1 -receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB 1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB 1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:163 |
|---|---|
| Enthalten in: |
Pain - 163(2022), 8 vom: 01. Aug., Seite 1603-1621 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Slivicki, Richard A [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 19.07.2022 Date Revised 18.08.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1097/j.pain.0000000000002550 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM334976081 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM334976081 | ||
| 003 | DE-627 | ||
| 005 | 20231225224834.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1097/j.pain.0000000000002550 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1116.xml |
| 035 | |a (DE-627)NLM334976081 | ||
| 035 | |a (NLM)34961756 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Slivicki, Richard A |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 19.07.2022 | ||
| 500 | |a Date Revised 18.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 International Association for the Study of Pain. | ||
| 520 | |a ABSTRACT: Activation of cannabinoid receptor type 1 (CB 1 ) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB 1 receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance, and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB 1 receptors to circumvent central CB 1 -related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB 1 -preferring agonist CB-13 on nociception and central CB 1 -related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB 1 -receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse dorsal root ganglion neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E 2 , providing potential mechanistic explanations for the analgesic actions of peripheral CB 1 receptor activation. With acute dosing, phenotypes associated with central CB 1 receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED 50 for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB 1 receptor dependence, even at a dose that did not produce central CB 1 -receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB 1 receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB 1 receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Analgesics |2 NLM | |
| 650 | 7 | |a Cannabinoid Receptor Agonists |2 NLM | |
| 650 | 7 | |a Naphthalenes |2 NLM | |
| 650 | 7 | |a Receptor, Cannabinoid, CB1 |2 NLM | |
| 650 | 7 | |a naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone |2 NLM | |
| 650 | 7 | |a 9XRJ6055XT |2 NLM | |
| 700 | 1 | |a Yi, Jiwon |e verfasserin |4 aut | |
| 700 | 1 | |a Brings, Victoria E |e verfasserin |4 aut | |
| 700 | 1 | |a Huynh, Phuong Nhu |e verfasserin |4 aut | |
| 700 | 1 | |a Gereau, Robert W |c 4th |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Pain |d 1993 |g 163(2022), 8 vom: 01. Aug., Seite 1603-1621 |w (DE-627)NLM000179205 |x 1872-6623 |7 nnns |
| 773 | 1 | 8 | |g volume:163 |g year:2022 |g number:8 |g day:01 |g month:08 |g pages:1603-1621 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1097/j.pain.0000000000002550 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 163 |j 2022 |e 8 |b 01 |c 08 |h 1603-1621 | ||