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. Protoporphyrin IX 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/cm). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared with SWISS mice because of 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, whereas antagonism of TRPA1 had no effect. These results suggest that products of singlet oxygen-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 PpIX-phototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria.

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

“…These findings led to the proposal of a mechanism whereby TRPA1 and TRPV1 are activated by ROS, RNS, and/or RCS generated from Fe 3ϩ -catalyzed conversion of oxysterols that are produced by peroxidation of 7-DHC by singlet oxygen resulting from photochemical reactions involving endogenous chromophores (54). In contrast, TRPV1, but not TRPA1, appears to be implicated in the action potential firing of mouse DRG neurons triggered by protoporphyrin IX phototoxicity produced by 630-nm light (900).…”

A randomized controlled trial evaluating the effects of transversus abdominis plane block with compound lidocaine hydrochloride injection on postoperative pain and opioid consumption and gastrointestinal motility in patients undergoing gynecological laparotomy

“…The longer duration of analgesia may be explained by the existence of menthol and glycerin in compound lidocaine injection. Several literatures have identified the local anesthetic and analgesic effects of menthol, and the activity of menthol to enhance tissue permeability and facilitate local anesthetic delivery ( Gaudioso et al, 2012 ; Liu et al, 2013 ; Castro and Dent, 2017 ; Oz et al, 2017 ; Pergolizzi Jr. et al, 2018 ; Wright et al, 2018 ). The viscosity of glycerin allows local anesthetics to remain locally for a longer time.…”

“…Menthol is well recognized for its pharmacological properties of persistent analgesia and anesthesia via cumulative inactivation of voltage-gated sodium channels, blockade of neuronal calcium ion channels, inhibition of inflammation, and desensitization of nociceptive receptors ( Gaudioso et al, 2012 ; Liu et al, 2013 ; Oz et al, 2017 ; Pergolizzi Jr. et al, 2018 ; Wright et al, 2018 ). Furthermore, menthol has become the primary active ingredient and permeation enhancer for several topical analgesic formulations in clinics ( Castro and Dent, 2017 ; Pergolizzi Jr. et al, 2018 ).…”

Adverse effects of topical photodynamic therapy: a consensus review and approach to management

“…A recent study also showed mechanistic differences between ALA and MAL, in that ALA‐PDT appeared to induce pain via singlet oxygen‐mediated lipid peroxidation, in turn triggering nociceptor activation via TRP cation channel subfamily V member 1 (TRPV1) receptors in dorsal root ganglia in vitro . Furthermore, the TRPV1 inhibitor menthol reduced action potentials evoked by ALA‐PDT in dorsal root ganglia and pain behaviour in a mouse model, although this was not the case with MAL‐PDT …”