Local nociceptor sensitization with NGF: Mechanical or heat hyperalgesia á la carte?

Abstract

In this issue, you will find a paper by C. Mills et al., (2013) entitled ‘Characterization of nerve growth factor induced mechanical and thermal hypersensitivity in the rat’. Nerve growth factor (NGF) has been found to sensitize pain processing already in the 1990s (Lewin et al.,1992; Woolf et al.,1994; Bennett et al.,1998; Koltzenburg et al.,1999; Kerr et al.,2001). Successful pain treatment using NGF antibodies (Lane et al.,2010; Katz et al.,2011; Schnitzer et al.,2011) has renewed the interest in this mechanism also inciting studies on human pain models applying NGF intramuscularly (Andersen et al.,2008; Svensson et al.,2008), in the muscle fascia (Deising et al.,2012) and in the skin of human volunteers (Rukwied et al.,2010; Weinkauf et al.,2012). Upon injection in the skin, NGF-induced mechanical and thermal hyperalgesia is found in animal models (Andreev et al.,1995). There are however, major differences in the time course of the hyperalgesia between tissues and between species. While the duration of hyperalgesia upon injection in the muscle is only a few days (Andersen et al.,2008; Svensson et al.,2008), intracutaneous injection in humans causes mechanical hyperalgesia lasting more than a month (Rukwied et al.,2010; Weinkauf et al.,2012). In rodents, heat and mechanical hyperalgesia have been reported to start hours after the injection and last hours or up to a couple of days. Mills and colleagues in this issue of European Journal of Pain report on a differential time course of heat and mechanical hyperalgesia in a rat model of NGF-induced hypersensitivity. Upon dermal injection of NGF, heat hyperalgesia was maximum after 3 h and had returned to baseline at 48 h. In contrast, mechanical hyperalgesia as measured with paw withdrawal threshold had developed 1 h after the injection but was significant for 1 week even for low NGF doses (0.3 μg) and for about 2 weeks at 3 μg. Interestingly, hypersensitivity to pin prick stimulation was significant only for the time point 1 h after the injection. The basis for the mismatch between pin prick hyperalgesia and withdrawal thresholds is unclear. However, one might suggest that the phasic pin prick tests are assessing behavioural pain threshold whereas the tonic nature of the paw pressure tests would allow more for suprathreshold testing. Along these lines, it is conceivable that the NGF-induced long-lasting mechanical hyperalgesia is based on sensitization of suprathreshold encoding as has similarly been found in the human NGF model (Rukwied et al.,2010), but also in the rat ultraviolet irradiation model (Bishop et al.,2010) in which high threshold mechanosensitive C-nociceptors were found to increase their firing upon suprathreshold mechanical stimulation, with their activation threshold being unchanged. The differential time course of mechanical and heat hypersensitivity resembles the delayed mechanical hyperalgesia observed in human volunteers and suggests different underlying mechanisms. While heat hyperalgesia might be based on sensitization and translocation of TRPV1, the prolonged mechanical sensitization might be linked to expression changes of axonal or sensory transduction proteins. The key implication of these results in respect to pharmacological testing is obviously the use of early and late hyperalgesia for separate testing of analgesic effects. The centrally acting analgesics morphine and gabapentin did not show a clear separation of their analgesic potency when comparing early and late phase or heat versus mechanical hyperalgesia. In contrast, duloxetin appeared to be more effective against the late mechanical hyperalgesia whereas the anti-inflammatory drugs Diclofenac and Celecoxib might be more effective in the early phase. In summary, the prolonged mechanical hyperalgesia as compared to the more transient heat hyperalgesia in the rat NGF model might allow for a better characterization of analgesic effects. Conflict of interest None declared.