Capsaicin induces degeneration of cutaneous autonomic nerve fibers

Abstract

Objective: To determine the effects of topical application of capsaicin on cutaneous autonomic nerves.

Methods: Thirty-two healthy subjects underwent occlusive application of 0.1% capsaicin cream (or placebo) for 48 hours. Subjects were followed for 6 months with serial assessments of sudomotor, vasomotor, pilomotor, and sensory function with simultaneous assessment of innervation through skin biopsies.

Results: There were reductions in sudomotor, vasomotor, pilomotor, and sensory function in capsaicin-treated subjects (p < 0.01 vs. placebo). Sensory function declined more rapidly than autonomic function, reaching a nadir by Day 6, whereas autonomic function reached a nadir by Day 16. There were reductions in sudomotor, vasomotor, pilomotor, and sensory nerve fiber densities in capsaicin-treated subjects (p < 0.01 vs. placebo). Intraepidermal nerve fiber density declined maximally by 6 days, whereas autonomic nerve fiber densities reached maximal degeneration by Day 16. Conversely, autonomic nerves generally regenerated more rapidly than sensory nerves, requiring 40-50 days to return to baseline levels, whereas sensory fibers required 140-150 days to return to baseline.

Interpretation: Topical capsaicin leads to degeneration of sudomotor, vasomotor, and pilomotor nerves accompanied by impairment of sudomotor, vasomotor, and pilomotor function. These results suggest the susceptibility and/or pathophysiologic mechanisms of nerve damage may differ between autonomic and sensory nerve fibers treated with capsaicin and enhances the capsaicin model for the study of disease-modifying agents. The data suggest caution should be taken when topical capsaicin is applied to skin surfaces at risk for ulceration, particularly in neuropathic conditions characterized by sensory and autonomic impairment.

Conflict of interest statement

Disclosure: The authors report no conflicts of interest.

Figures

Fig 1

Outline of the test paradigm on the forearm. The capsaicin treated area is divided into quadrants for structural and functional assessments: laser Doppler flowmetry to measure cutaneous vasomotor function, quantitative sensory testing (QST) to measure sensory function, silicone impressions to measure pilomotor function, quantitative sudomotor axon reflex testing (QSART) to measure sudomotor function and skin biopsies to quantify autonomic and sensory nerve fiber density.

Fig 2

The change over time in cutaneous autonomic and sensory nerve fiber structure (Panels A, C, E, G) and function (Panels B, D, F, H) in capsaicin treated (closed black circles) and placebo treated subjects (open white circles). The results are expressed as percent of baseline for all panels. All results (A-H) were significant at p<0.01 compared to placebo treated subjects (ANOVA). A decrease in measures of structure and function is seen between days 3–16 after capsaicin treatment. There are no corresponding changes in the placebo-treated group. Increases in heat and heat-pain thresholds (Panel G) implies a greater temperature is required to reach threshold.

Fig 3

The effects of capsaicin on sudomotor nerves. Panels A and B: The sweat gland (green) and associated innervation (red) in a Day 16 control (A) and capsaicin-treated (B) biopsy. Fewer nerve fibers are visible in the capsaicin treated compared to the control treated biopsy. Red bar (A & B) = 100 μm. Panel C: The calculated sudomotor nerve fiber density in the control (black bar) and capsaicin (white bar) treated regions at day 16. There is a significant reduction in nerve fibers in the capsaicin treated area (p<0.01). Panel D: The maximum change in sudomotor function measured by QSART. There is a significant decrease in sweat output in the capsaicin treated region (p<0.01).

Fig 4

The effects of capsaicin on vasomotor nerves. Panels A and B: The cutaneous vasculature stained by CD 31 (green) and the associated innervation (red) stained by PGP 9.5 in a representative Day 16 control (A) and capsaicin treated (B) biopsy. The epithelial border is seen at the top of the image (white arrowheads). Fewer nerve fibers (yellow arrows) are visible in the Day 16 capsaicin-treated than control biopsy. Panel C: The vasomotor density for the control- (black bar) and capsaicin-treated (white bar) regions at day 16. There is a significant nerve fiber reduction in the capsaicin treated area (p<0.01). Panel D: Vasomotor function for the control- (black bar) and capsaicin-treated (white bar) regions at day 16. There is a significant axon reflex mediated flare response reduction in the capsaicin treated area (p<0.01). Scale bar (A & B) = 200 μm.

Fig 5

The effects of capsaicin on pilomotor nerves. Panels A and B: An arrector pili muscle is seen with nerve fibers extending parallel to the muscle in a control (A) and capsaicin-treated (B) biopsy stained with PGP 9.5. Fewer nerve fibers are visible in the capsaicin-treated compared to control on Day 16. Scale bar (A & B) = 200 μm. Panel C: Pilomotor nerve fiber density in the control regions (black bar) is significantly higher than the capsaicin treated regions (white bar) regions at day 16 (p<0.01). Panel D. Arrector pili, when electrically stimulated, cause piloerection (goose-bumps) that can be quantified with silicone impressions. The red circle surrounds a representative ‘goose-bump’ in a Day 16 control subject. Panel E: In a representative Day 16 capsaicin treated region, the stimulated arrector pili muscles form smaller impressions (red circle). Panel F: The mean area of piloerection is greater in control regions (black bar) compared to the capsaicin treated regions (white bar) (p<0.01).

Fig 6

The effects of capsaicin on sensory nerves. Panels A and B: The epidermal innervation stained by PGP 9.5 (green) penetrating the epidermal layer (yellow arrow) in a representative Day 16 control (A) and capsaicin-treated (B) biopsy. Fewer nerve fibers (green) are visible in the Day 16 capsaicin-treated than control biopsy. Scale bar (A & B) = 100 μm. Panel C: The intra-epidermal nerve fiber density (IENFD) for the control- (black bar) and capsaicin-treated (white bar) regions at day 16. There is a significant nerve fiber reduction in the capsaicin treated area (p<0.01). (D) The thermal and thermal-pain stimulation thresholds for control (black bar) and capsaicin (white bar) treated regions. There is a reduction in cold detection thresholds and an increase in heat and heat-pain (HP) detection thresholds in the capsaicin-treated regions at day 16 compared to control treated regions. *p<0.05.

Fig 7

The rates of nerve fiber degeneration (A) and regeneration (B) by nerve fiber subtype. Panel A: The lines represent the percent change from baseline on day 1 to the day of maximal change. Sensory nerve fibers degenerate and sensory function decreases more rapidly than autonomic nerve fibers. Vasomotor function declines at a rate between that of sensory and autonomic function most likely in part due to physiologic desensitization and neuropeptide depletion. Panel B: The lines represent the time required for nerve fiber subtypes to return to baseline levels from the day of maximal degeneration (return to baseline levels defined as a non-significant change from baseline). Structural regeneration and functional improvement is more rapid in autonomic nerve fibers than in sensory nerve fibers. Vasomotor nerves, vasomotor function and cold detection thresholds return to baseline at a rate between sensory and other autonomic nerve fiber types.