Menthol reduces phototoxicity pain in a mouse model of photodynamic therapy

Lisa Wright, Daniel Baptista-Hon, Fiona Bull, Faith Dalgaty, Michael Gallacher, Sally H. Ibbotson, Tim G. Hales (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

Phototoxicity-induced pain is a major clinical problem triggered by light acting on photosensitising drugs or endogenous porphyrins, notably protoporphyrin IX (PpIX), an intermediary in heme biosynthesis. PpIX accumulates in individuals with erythropoietic protoporphyria and is elevated during photodynamic therapy subsequent to application of 5- aminolevulinic acid (ALA). Pain occurs during irradiation of PpIX and responds poorly to conventional analgesics. Our objective was to develop a model of PpIX phototoxicity pain and investigate the potential of menthol as an analgesic. Application of ALA to the tails of C57 black and SWISS white mice caused PpIX accumulation and nociception during irradiation (630 nm at 3.7 J/cm2 ). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared to SWISS mice due to light absorption by pigmentation. Irradiation of ALA-treated dorsal root ganglion neurons caused phototoxicity-evoked action potentials (APs) in both mouse strains. The antioxidant L-tryptophan increased the light dose required to elicit such APs. By contrast, the addition of keratinocytes to neuronal cultures decreased the threshold for APs, suggesting a requirement for proliferating cells. Inhibition of fatty acid amide hydrolase, selective antagonism of TRPV1 or the application of lidocaine or its quaternary derivative QX-314, reduced AP frequency, while antagonism of TRPA1 had no effect. These results suggest that products of singlet O2-mediated lipid peroxidation trigger nociceptor activation via TRPV1. Menthol inhibited phototoxicity-evoked APs and reduced pain behavior when applied topically to mice. These findings suggest that menthol might provide pain relief in patients experiencing PpIXphototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria.
Original languageEnglish
Pages (from-to)284-297
Number of pages14
JournalPain
Volume159
Issue number2
Early online date25 Nov 2017
DOIs
Publication statusPublished - 1 Feb 2018

Fingerprint

Menthol
Phototoxic Dermatitis
Photochemotherapy
Action Potentials
Pain
Aminolevulinic Acid
Erythropoietic Protoporphyria
Evoked Potentials
Analgesics
Light
Nociceptors
Nociception
Porphyrins
Pigmentation
Spinal Ganglia
Lidocaine
Heme
Keratinocytes
Tryptophan
Lipid Peroxidation

Keywords

  • Phototoxicity
  • photosensitisation
  • porphyria
  • reactive oxygen species
  • electrophysiology
  • behavioral neuroscience
  • Porphyria
  • Photosensitisation
  • Reactive oxygen species
  • Electrophysiology
  • Behavioral neuroscience

Cite this

@article{3e39b0c56e7746dabfacd66170e09472,
title = "Menthol reduces phototoxicity pain in a mouse model of photodynamic therapy",
abstract = "Phototoxicity-induced pain is a major clinical problem triggered by light acting on photosensitising drugs or endogenous porphyrins, notably protoporphyrin IX (PpIX), an intermediary in heme biosynthesis. PpIX accumulates in individuals with erythropoietic protoporphyria and is elevated during photodynamic therapy subsequent to application of 5- aminolevulinic acid (ALA). Pain occurs during irradiation of PpIX and responds poorly to conventional analgesics. Our objective was to develop a model of PpIX phototoxicity pain and investigate the potential of menthol as an analgesic. Application of ALA to the tails of C57 black and SWISS white mice caused PpIX accumulation and nociception during irradiation (630 nm at 3.7 J/cm2 ). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared to SWISS mice due to light absorption by pigmentation. Irradiation of ALA-treated dorsal root ganglion neurons caused phototoxicity-evoked action potentials (APs) in both mouse strains. The antioxidant L-tryptophan increased the light dose required to elicit such APs. By contrast, the addition of keratinocytes to neuronal cultures decreased the threshold for APs, suggesting a requirement for proliferating cells. Inhibition of fatty acid amide hydrolase, selective antagonism of TRPV1 or the application of lidocaine or its quaternary derivative QX-314, reduced AP frequency, while antagonism of TRPA1 had no effect. These results suggest that products of singlet O2-mediated lipid peroxidation trigger nociceptor activation via TRPV1. Menthol inhibited phototoxicity-evoked APs and reduced pain behavior when applied topically to mice. These findings suggest that menthol might provide pain relief in patients experiencing PpIXphototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria.",
keywords = "Phototoxicity, photosensitisation, porphyria, reactive oxygen species, electrophysiology, behavioral neuroscience, Porphyria, Photosensitisation, Reactive oxygen species, Electrophysiology, Behavioral neuroscience",
author = "Lisa Wright and Daniel Baptista-Hon and Fiona Bull and Faith Dalgaty and Michael Gallacher and Ibbotson, {Sally H.} and Hales, {Tim G.}",
note = "This work was supported by Tenovus Scotland (TGH) and a Wellcome Trust PhD Fellowship to (FB). We thank Dr Zhihong Huang and Fan Zhang for the infrared camera and assistance with the thermal imaging experiment, the Behavioural Neuroscience Core Facility for assistance with behavioural tests and Claire Sneddon for doing some of the dissections. We would also like to acknowledge the support of the Scottish PDT Centre for the provision of technical input and laser equipment. The authors declare that no conflict of interest exists.",
year = "2018",
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Menthol reduces phototoxicity pain in a mouse model of photodynamic therapy. / Wright, Lisa; Baptista-Hon, Daniel; Bull, Fiona; Dalgaty, Faith; Gallacher, Michael; Ibbotson, Sally H.; Hales, Tim G. (Lead / Corresponding author).

In: Pain, Vol. 159, No. 2, 01.02.2018, p. 284-297.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Menthol reduces phototoxicity pain in a mouse model of photodynamic therapy

AU - Wright, Lisa

AU - Baptista-Hon, Daniel

AU - Bull, Fiona

AU - Dalgaty, Faith

AU - Gallacher, Michael

AU - Ibbotson, Sally H.

AU - Hales, Tim G.

N1 - This work was supported by Tenovus Scotland (TGH) and a Wellcome Trust PhD Fellowship to (FB). We thank Dr Zhihong Huang and Fan Zhang for the infrared camera and assistance with the thermal imaging experiment, the Behavioural Neuroscience Core Facility for assistance with behavioural tests and Claire Sneddon for doing some of the dissections. We would also like to acknowledge the support of the Scottish PDT Centre for the provision of technical input and laser equipment. The authors declare that no conflict of interest exists.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Phototoxicity-induced pain is a major clinical problem triggered by light acting on photosensitising drugs or endogenous porphyrins, notably protoporphyrin IX (PpIX), an intermediary in heme biosynthesis. PpIX accumulates in individuals with erythropoietic protoporphyria and is elevated during photodynamic therapy subsequent to application of 5- aminolevulinic acid (ALA). Pain occurs during irradiation of PpIX and responds poorly to conventional analgesics. Our objective was to develop a model of PpIX phototoxicity pain and investigate the potential of menthol as an analgesic. Application of ALA to the tails of C57 black and SWISS white mice caused PpIX accumulation and nociception during irradiation (630 nm at 3.7 J/cm2 ). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared to SWISS mice due to light absorption by pigmentation. Irradiation of ALA-treated dorsal root ganglion neurons caused phototoxicity-evoked action potentials (APs) in both mouse strains. The antioxidant L-tryptophan increased the light dose required to elicit such APs. By contrast, the addition of keratinocytes to neuronal cultures decreased the threshold for APs, suggesting a requirement for proliferating cells. Inhibition of fatty acid amide hydrolase, selective antagonism of TRPV1 or the application of lidocaine or its quaternary derivative QX-314, reduced AP frequency, while antagonism of TRPA1 had no effect. These results suggest that products of singlet O2-mediated lipid peroxidation trigger nociceptor activation via TRPV1. Menthol inhibited phototoxicity-evoked APs and reduced pain behavior when applied topically to mice. These findings suggest that menthol might provide pain relief in patients experiencing PpIXphototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria.

AB - Phototoxicity-induced pain is a major clinical problem triggered by light acting on photosensitising drugs or endogenous porphyrins, notably protoporphyrin IX (PpIX), an intermediary in heme biosynthesis. PpIX accumulates in individuals with erythropoietic protoporphyria and is elevated during photodynamic therapy subsequent to application of 5- aminolevulinic acid (ALA). Pain occurs during irradiation of PpIX and responds poorly to conventional analgesics. Our objective was to develop a model of PpIX phototoxicity pain and investigate the potential of menthol as an analgesic. Application of ALA to the tails of C57 black and SWISS white mice caused PpIX accumulation and nociception during irradiation (630 nm at 3.7 J/cm2 ). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared to SWISS mice due to light absorption by pigmentation. Irradiation of ALA-treated dorsal root ganglion neurons caused phototoxicity-evoked action potentials (APs) in both mouse strains. The antioxidant L-tryptophan increased the light dose required to elicit such APs. By contrast, the addition of keratinocytes to neuronal cultures decreased the threshold for APs, suggesting a requirement for proliferating cells. Inhibition of fatty acid amide hydrolase, selective antagonism of TRPV1 or the application of lidocaine or its quaternary derivative QX-314, reduced AP frequency, while antagonism of TRPA1 had no effect. These results suggest that products of singlet O2-mediated lipid peroxidation trigger nociceptor activation via TRPV1. Menthol inhibited phototoxicity-evoked APs and reduced pain behavior when applied topically to mice. These findings suggest that menthol might provide pain relief in patients experiencing PpIXphototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria.

KW - Phototoxicity

KW - photosensitisation

KW - porphyria

KW - reactive oxygen species

KW - electrophysiology

KW - behavioral neuroscience

KW - Porphyria

KW - Photosensitisation

KW - Reactive oxygen species

KW - Electrophysiology

KW - Behavioral neuroscience

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DO - 10.1097/j.pain.0000000000001096

M3 - Article

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ER -