Inflammation meets sensitization—an explanation for spontaneous nociceptor activity?

• Published in: Pain (Amsterdam) Vol. 154; no. 12; pp. 2707 - 2714
• Main Authors: Rukwied, Roman, Weinkauf, Benjamin, Main, Maurice, Obreja, Otilia, Schmelz, Martin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.12.2013; International Association for the Study of Pain; Elsevier
• Subjects: Adult; Axonal excitability; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Hot Temperature - adverse effects; Humans; Inflammation - diagnosis; Inflammation - physiopathology; Male; Middle Aged; NaV; Nerve Growth Factor - toxicity; NGF; Nociceptors - physiology; Pain; Pain - chemically induced; Pain - diagnosis; Pain - physiopathology; Pain Measurement - methods; Physical Stimulation - adverse effects; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Ultraviolet Rays - adverse effects; UV-B; Vertebrates: nervous system and sense organs; Young Adult; UV-B; NaV; Pain; Axonal excitability; NGF; Nociceptor; Excitability; Nerve growth factor; Inflammation; Sensitization
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1016/j.pain.2013.07.054

Experimental combination of nerve growth factor (NGF) evoked sensitization and ultraviolet-B (UV-B)–induced inflammation causes spontaneous pain and supra-additive hyperalgesia in human beings. The data reinforce therapeutic analgesic anti-NGF strategies. 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 3weeks 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 (100kPa for 10seconds, peak VAS 58±7 vs VAS 21±5 [NGF] and VAS 12±3 [UV-B]) and pinprick (150mN for 5seconds, 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 24hours 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.