Inflammation meets sensitization--an explanation for spontaneous nociceptor activity?
Anti-nerve growth factor (anti-NGF) treatment is analgesic in chronic inflammatory pain conditions without reducing inflammation. Hypothesizing that ongoing pain induced by inflammatory mediators is increased by long term sensitization of nociceptors, we combined the non-inflammatory NGF-sensitization model with an inflammatory ultraviolet-B (UV-B) model in human volunteers. UV-B irradiation of the skin presensitized with NGF 3 weeks before intensified the pre-existing NGF hyperalgesia during the inflammatory phase of UV-B and caused spontaneous pain in about 70% of the subjects. Pain levels paralleled the intensity of UVB inflammation. Hyperalgesia recorded on a VAS (0-100) was additive after combined NGF/UV-B treatment versus single NGF or UV-B treatment for mechanical impact and tonic heat stimuli, again paralleling the intensity of the UV-B inflammation. In contrast, ratings to tonic mechanical pressure (100 kPa for 10 seconds, peak VAS 58 ± 7 vs VAS 21 ± 5 [NGF] and VAS 12 ± 3 [UV-B]) and pinprick (150 mN for 5 seconds, peak VAS 33 ± 7 vs VAS 10 ± 2 [NGF] and VAS 8 ± 3 [UV-B]) increased in a supra-additive manner. This supra-additive effect faded 24 hours after irradiation, although heat sensitization remained increased. Hyperalgesia and spontaneous pain coexisted in NGF/UV-B treated skin but did not significantly correlate (r < -0.1 at day 1 and r < 0.2 at day 3). We conclude that NGF can sensitize nociceptive endings such that inflammatory mediators may cause sufficient excitation to provoke spontaneous pain. Our results suggest that neuronal sensitization and level of inflammation represent independent therapeutic targets in chronic inflammatory pain conditions.
Department of Anaesthesiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Roman
R
Rukwied
Benjamin
B
Weinkauf
Maurice
M
Main
Otilia
O
Obreja
Martin
M
Schmelz
D000328:Adult; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000633:toxicity*; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods*; D010812:Physical Stimulation / Q000009:adverse effects; D014466:Ultraviolet Rays / Q000009:adverse effects*; D055815:Young Adult
D020932:Nerve Growth Factor
Axonal excitability; NGF; NaV; Pain; UV-B