Cargando…

Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy

Cisplatin is a widely used platinum-derived antineoplastic agent that frequently results in peripheral neuropathy. Therapeutic strategies for neuropathic pain are limited and characterized by variable efficacy and severe adverse effects. Clinical translation of novel analgesics has proven difficult...

Descripción completa

Detalles Bibliográficos
Autores principales: Thompson, Jeremy M, Blanton, Henry L, Pietrzak, Agata, Little, William, Sherfey, Caitlyn, Guindon, Josée
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757502/
https://www.ncbi.nlm.nih.gov/pubmed/31418316
http://dx.doi.org/10.1177/1744806919874192
_version_ 1783453585470652416
author Thompson, Jeremy M
Blanton, Henry L
Pietrzak, Agata
Little, William
Sherfey, Caitlyn
Guindon, Josée
author_facet Thompson, Jeremy M
Blanton, Henry L
Pietrzak, Agata
Little, William
Sherfey, Caitlyn
Guindon, Josée
author_sort Thompson, Jeremy M
collection PubMed
description Cisplatin is a widely used platinum-derived antineoplastic agent that frequently results in peripheral neuropathy. Therapeutic strategies for neuropathic pain are limited and characterized by variable efficacy and severe adverse effects. Clinical translation of novel analgesics has proven difficult with many agents demonstrating preclinical efficacy failing in clinical trials. Preclinical studies frequently assess pain behaviors in the hind paws; however, the front paws have a greater degree of the fine sensorimotor functions characteristically damaged by chemotherapy-induced neuropathy. This is the first study to assess pain responses in the front paws. Here, we test the hypothesis that mouse front paws exhibit pain-related alterations in mechanical and thermal (cold) sensitivity in a murine model of cisplatin-induced neuropathy and that pharmacological treatment with amitriptyline, gabapentin, ibuprofen, and URB937 normalize pain behaviors in the front and hind paws. Cold (acetone withdrawal latencies) and mechanical (von Frey withdrawal thresholds) sensitivity were significantly increased and decreased respectively in both the front and the hind paws following initiation of weekly systemic (intraperitoneal) cisplatin injections (5 mg/kg). For the hind paws, systemic administration of amitriptyline (30 mg/kg), gabapentin (100 mg/kg), ibuprofen (0–10 mg/kg), or URB937 (0–10 mg/kg) resulted in a decrease in acetone withdrawal latencies and increase in von Frey withdrawal thresholds with return to normal values at the highest doses tested. For the front paws, return to baseline values for the highest doses was found for cold allodynia but not mechanical allodynia, where the highest doses failed to return to baseline values. These results indicate that mouse front paws exhibit pain-related changes in cisplatin-induced neuropathy and that drug effects can vary based on testing stimulus and location. This suggests that front paw responses across multiple modalities provide reliable and accurate information about pain-related drug effects. Future studies should be aimed at elucidating the mechanisms underlying these differential effects.
format Online
Article
Text
id pubmed-6757502
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher SAGE Publications
record_format MEDLINE/PubMed
spelling pubmed-67575022019-10-02 Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy Thompson, Jeremy M Blanton, Henry L Pietrzak, Agata Little, William Sherfey, Caitlyn Guindon, Josée Mol Pain Research Article Cisplatin is a widely used platinum-derived antineoplastic agent that frequently results in peripheral neuropathy. Therapeutic strategies for neuropathic pain are limited and characterized by variable efficacy and severe adverse effects. Clinical translation of novel analgesics has proven difficult with many agents demonstrating preclinical efficacy failing in clinical trials. Preclinical studies frequently assess pain behaviors in the hind paws; however, the front paws have a greater degree of the fine sensorimotor functions characteristically damaged by chemotherapy-induced neuropathy. This is the first study to assess pain responses in the front paws. Here, we test the hypothesis that mouse front paws exhibit pain-related alterations in mechanical and thermal (cold) sensitivity in a murine model of cisplatin-induced neuropathy and that pharmacological treatment with amitriptyline, gabapentin, ibuprofen, and URB937 normalize pain behaviors in the front and hind paws. Cold (acetone withdrawal latencies) and mechanical (von Frey withdrawal thresholds) sensitivity were significantly increased and decreased respectively in both the front and the hind paws following initiation of weekly systemic (intraperitoneal) cisplatin injections (5 mg/kg). For the hind paws, systemic administration of amitriptyline (30 mg/kg), gabapentin (100 mg/kg), ibuprofen (0–10 mg/kg), or URB937 (0–10 mg/kg) resulted in a decrease in acetone withdrawal latencies and increase in von Frey withdrawal thresholds with return to normal values at the highest doses tested. For the front paws, return to baseline values for the highest doses was found for cold allodynia but not mechanical allodynia, where the highest doses failed to return to baseline values. These results indicate that mouse front paws exhibit pain-related changes in cisplatin-induced neuropathy and that drug effects can vary based on testing stimulus and location. This suggests that front paw responses across multiple modalities provide reliable and accurate information about pain-related drug effects. Future studies should be aimed at elucidating the mechanisms underlying these differential effects. SAGE Publications 2019-09-23 /pmc/articles/PMC6757502/ /pubmed/31418316 http://dx.doi.org/10.1177/1744806919874192 Text en © The Author(s) 2019 http://creativecommons.org/licenses/by/4.0/ Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Research Article
Thompson, Jeremy M
Blanton, Henry L
Pietrzak, Agata
Little, William
Sherfey, Caitlyn
Guindon, Josée
Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
title Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
title_full Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
title_fullStr Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
title_full_unstemmed Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
title_short Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
title_sort front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and urb937 on mechanical and cold sensitivity in cisplatin-induced neuropathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757502/
https://www.ncbi.nlm.nih.gov/pubmed/31418316
http://dx.doi.org/10.1177/1744806919874192
work_keys_str_mv AT thompsonjeremym frontandhindpawdifferentialanalgesiceffectsofamitriptylinegabapentinibuprofenandurb937onmechanicalandcoldsensitivityincisplatininducedneuropathy
AT blantonhenryl frontandhindpawdifferentialanalgesiceffectsofamitriptylinegabapentinibuprofenandurb937onmechanicalandcoldsensitivityincisplatininducedneuropathy
AT pietrzakagata frontandhindpawdifferentialanalgesiceffectsofamitriptylinegabapentinibuprofenandurb937onmechanicalandcoldsensitivityincisplatininducedneuropathy
AT littlewilliam frontandhindpawdifferentialanalgesiceffectsofamitriptylinegabapentinibuprofenandurb937onmechanicalandcoldsensitivityincisplatininducedneuropathy
AT sherfeycaitlyn frontandhindpawdifferentialanalgesiceffectsofamitriptylinegabapentinibuprofenandurb937onmechanicalandcoldsensitivityincisplatininducedneuropathy
AT guindonjosee frontandhindpawdifferentialanalgesiceffectsofamitriptylinegabapentinibuprofenandurb937onmechanicalandcoldsensitivityincisplatininducedneuropathy