Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans

Abstract

Nerve growth factor (NGF) plays a biologic role in the development and maintenance of sympathetic and small sensory neurons. Because it facilitates nerve fiber regeneration, lowers heat-pain threshold (hyperalgesia), and prevents or improves nerve dysfunction in experimental neuropathy, it is being considered as a putative treatment for certain human polyneuropathies. In 16 healthy subjects, we tested whether intradermal injection of minute doses of recombinant human NGF (1 or 3 micrograms) compared with saline induces hyperalgesia or alters cutaneous sensation (at the site of injection) as measured by symptom scores, clinical examination, or quantitative sensory testing with Computer Assisted Sensory Examination (CASE IV). Most subjects had, as their only symptom, localized tenderness of the NGF-injected site and only when the site was bumped or compressed. Slight discomfort developed in volar wrist structures (with flexion of fingers) or tenderness of deep structures to palpation over the bicipital groove or supraclavicular region. The Neuropathy Symptoms and Change questionnaire indicated that pressure allodynia was significantly localized to the NGF-injected side from 3 hours to 21 days after injections. Light stroking of the skin did not induce tactile allodynia. Compression of injected sites induced pressure allodynia that occurred more frequently and significantly on the NGF-injected side after 3 hours and was maintained for several weeks. No abnormality of vibratory or cooling detection threshold developed from NGF injection. By contrast, heat-pain threshold (HP 0.5, p = 0.003) and an intermediate level of heat-pain (HP 5.0, p < 0.001) were significantly lowered 1, 3, and 7 days (and in some cases at 3 hours and 14 and 21 days) after NGF injection. The time course of pressure allodynia and heat-pain hyperalgesia is too rapid to be explained by uptake of NGF by nociception terminals, retrograde transport, and upregulation of pain modulators. Local tissue mechanisms appear to be implicated. It remains to be tested whether recombinant human NGF prevents, stabilizes, or ameliorates small fiber human neuropathies.

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

“…One early study noted signs of mechanical hyperalgesia within 6 hours of an injection of rhNGF into the skin (Dyck et al, 1997). However, later studies using the same approach in humans showed that hyperalgesia, as measured using pressure pain threshold or pinprick sensitivity, first appears after 7 days and peaks 21 days after an intradermal rhNGF injection (Rukwied et al, 2010Obreja et al, 2011a;.…”

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

“…NGF is implicated in mediating inflammatory hyperalgesia because (1) administration of NGF leads to hyperalgesia in adult rats Woolf et al, 1994) and in humans (Petty et al, 1994;Dyck et al, 1997), (2) it sensitizes nociceptive neurons (Dmitrieva and McMahon, 1996;Rueff and Mendell, 1996), (3) transgenic mice that overexpress NGF in skin are hyperalgesic (Davis et al, 1993), and (4) neutralization of endogenous NGF blocks inflammation-induced hyperalgesia and sensitization (Woolf et al, 1994;McMahon et al, 1995;Koltzenburg et al, 1999). Because inflammatory hyperalgesia is NGFdependent, sequestration of NGF should reverse membrane changes that contribute to it.…”

Glial Cell Line-Derived Neurotrophic Factor Family Members Sensitize NociceptorsIn Vitroand Produce Thermal HyperalgesiaIn Vivo

“…In both rodents and humans, in vivo injection of NGF produces thermal hypersensitivity within 30 min and mechanical sensitivity within hours (Lewin et al, 1994;Dyck et al, 1997). In vitro, NGF sensitizes the transient receptor potential vanilloid type 1 (TRPV1) receptor Mendell, 1999a, 2001;Zhu et al, 2004).…”