Desensitization of Nociceptive Afferents by Application of Topical Capsaicin, Trans-cinnamaldehyde and L-menthol

Desensitization of Nociceptive Afferents by Application of Topical Capsaicin, Trans-cinnamaldehyde and L-menthol

Temporal Profile of the Nociceptive Desensitization Induced by 8% Topical Capsaicin and the Functional Independence of Transient Receptor Potential Ankyrin 1 (TPRA1)- and Vanilloid 1 (TRPV1)-Expressing Nociceptive Afferents

The purpose of this study is to investigate the potential desensitising effects of repeated applications of capsaicin, trans-cinnamaldehyde and L-menthol on thermal, mechanical and chemical sensory stimulations.

Capsaicin, the compound responsible for the pungency of chili peppers, can induce desensitization to nociceptive (1) and pruriceptive (2) stimuli when topically applied. The purpose of this study is to determine whether repeated topical applications of trans-cinnamaldehyde and L-menthol result in decreased responses to various nociceptive and non-nociceptive thermal and mechanical stimuli and to compare potential alterations with those caused by repeated topical application of capsaicin. Furthermore, this study investigates the temporal profile of said alterations. Capsaicin 8% patches, trans-cinnamaldehyde 10%, L-menthol 40% and inert vehicle patches will each be applied to 4 4x4 cm predefined areas on the skin of the volar forearms for 1 hour 4 times on 4 consecutive days. Before each application and the day after the last application, cold detection threshold (CDT), warmth detection threshold (WDT), cold pain threshold (CPT) and heat pain threshold (HPT) will be assessed using a Medoc Pathway (Medoc, Israel) equipped with a 3x3 cm contact thermode. On the last day, mechanical detection threshold (MDT) is assessed using a series of von Frey filaments and mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS) is assessed using a series of standardized pinprick stimulators (Aalborg University). Furthermore, full-field laser perfusion imaging (FLPI) will be used to assess the degree of neurogenic inflammation in each predefined area before and after each substance application and at the last session. F. Henrich et al. 2015 "Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans" H.H. Andersen et al. 2017 "Antipruritic effect of pretreatment with 8% topical capsaicin on histamine- and cowhage-evoked itch in healthy volunteers - a randomized placebo-blinded proof-of-concept trial"

Capsacin (8%) patches applied topically 4 times for 1 hour to a 4x4 cm predefined area on the skin of the volar forearms.

Trans-cinnamaldehyde (10%, dissolved in 90% ethanol) applied topically 4 times for 1 hour to a 4x4 cm predefined area on the skin of the volar forearms on a cotton ball placed in a plastic chamber to limit evaporation.

L-menthol (40%, dissolved in 96% ethanol) applied topically 4 times for 1 hour to a 4x4 cm predefined area on the skin of the volar forearms on a cotton ball placed in a plastic chamber to limit evaporation.

Inert vehicle patches applied topically 4 times for 1 hour to a 4x4 cm predefined area on the skin of the volar forearms.

4x4 cm patch of 8% topical capsaicin applied to the skin of the volar forearm for 1 hour 4 times on 4 consecutive days

1mL of 10% trans-cinnamaldehyde applied to the skin of the volar forearm for 1 hour 4 times on 4 consecutive days

1mL of 40% L-menthol applied to the skin of the volar forearm for 1 hour 4 times on 4 consecutive days

Inert vehicle patch applied to the skin of the volar forearm for 1 hour 4 times on 4 consecutive days

The pain threshold for cold stimulation assessed using a Medoc Pathway (Medoc, Israel) equipped with a 3x3 cm thermode. CPT is defined as the temperature at which cold induces pain and is expressed in °C.

The average intensity of the neurogenic inflammation as assessed by full-field laser perfusion imaging (FLPI) (expressed in arbitrary units)

The area of the neurogenic inflammation as assessed by full-field laser perfusion imaging (FLPI) (expressed in arbitrary units)

Pain during the 60 minute application of topical capsaicin as rated on a visual analog scale (VAS) (0-10)

Assessed every 5 minutes during the 60 minute application of capsaicin at 4 visits on 4 consecutive days

Pain during the 60 minute application of trans-cinnamaldehyde as rated on a visual analog scale (VAS) (0-10)

Assessed every 5 minutes during the 60 minute application of trans-cinnamaldehyde at 4 visits on 4 consecutive days

Assessed every 5 minutes during the 60 minute application of L-menthol at 4 visits on 4 consecutive days

Pain during the 60 minute application of the inert patch (control) as rated on a visual analog scale (VAS) (0-10)

Assessed every 5 minutes during the 60 minute application of the inert patch (control) at 4 visits on 4 consecutive days

The detection threshold for cold stimulation assessed using a Medoc Pathway (Medoc, Israel) equipped with a 3x3 cm thermode. CDT is defined as the temperature at which cold can be detected and is expressed in °C.

The detection threshold for warmth stimulation assessed using a Medoc Pathway (Medoc, Israel) equipped with a 3x3 cm thermode. WDT is defined as the temperature at which warmth can be detected and is expressed in °C.

The detection threshold for mechanical stimulation is defined as the smallest force that can be felt and is assessed using a series of standardized von Frey filaments and using the "method of limits" employing a series of stimulations with ascending and descending force expressed in mN.

The pain threshold for mechanical stimulation is defined as the smallest force that induces pain and is assessed using a series of standardized pinprick stimulators (Aalborg University) and using the "method of limits" employing a series of stimulations with ascending and descending forces expressed in mN.

The sensitivity to mechanically induced pain induced by a series of 7 standardized pinprick stimulators (Aalborg University) as rated on a visual analog scale (VAS) ranging from 0-10 with 0 representing no pain and 10 representing the worst pain imaginable.

Inclusion Criteria: Healthy Speaks and understands English or Danish 18-60 years Exclusion Criteria: Pregnancy or lactation Drug addiction Previous or current dermatological, neurological, musculoskeletal or mental illnesses Lack of ability to cooperate Current use of medications that may affect the trial