Nerve growth factor-induced hyperalgesia in the neonatal and adult rat

Abstract

Recently, we have shown that the interaction between NGF and sensory neurons in early postnatal periods is restricted to nociceptive afferents (Ritter et al., 1991; Lewin et al., 1992a; Ritter and Mendell, 1992). Here we show that administration of excess NGF to neonatal or mature animals can lead to a profound behavioral hyperalgesia. Neonatal NGF treatment (postnatal day 0-14) resulted in a profound mechanical hyperalgesia that persisted until the animals had reached maturity (6 weeks of age). This hyperalgesia could be explained by an NGF-mediated sensitization of A delta nociceptive afferents to mechanical stimuli. This peripheral sensitization wore off with a time course similar to that of the behavior hyperalgesia. Treatment of animals from the second postnatal week until 5 weeks of age (juveniles) led to a very similar behavioral hyperalgesia; however, there was no corresponding sensitization of A delta nociceptors to mechanical stimuli. Finally, one group of adult animals (5 weeks old) was treated daily with single injections of NGF for between 1 and 4 d. Within 24 hr after the first NGF injection these animals developed a mechanical hyperalgesia of the same magnitude seen after neonatal and juvenile NGF treatments. No sensitization of A delta nociceptive afferents was observed in these animals. In addition to the mechanical hyperalgesia, the animals also developed a heat hyperalgesia after one injection of NGF. The heat hyperalgesia was apparent within 15 min after the injection; however, signs of mechanical hyperalgesia were not seen until 6 hr after the injection. In conclusion, it appears that the NGF-induced mechanical hyperalgesia is brought about by different mechanisms in neonatal and adult rats. Furthermore, in adult animals the NGF-induced mechanical and heat hyperalgesia also appear to be attributable to two different mechanisms. The mechanical hyperalgesia may be due to central changes (see Lewin et al., 1992b), whereas the heat hyperalgesia is likely to result at least in part from the sensitization of peripheral receptors to heat.

Nerve Growth Factor- and Neurotrophin-3-Induced Changes in Nociceptive Threshold and the Release of Substance P from the Rat Isolated Spinal Cord

“…This study confirms that single systemic administration of NGF to the rat induces thermal and mechanical hyperalgesia (Lewin et al, 1993). Thermal hyperalgesia developed as soon as 30 min after injection (early component) and persisted for up to 24 hr (late component), whereas mechanical hyperalgesia started 24 hr after injection and persisted for up to 48 hr.…”

“…Systemic administration of a single dose of NGF induces mechanical and thermal hyperalgesia in adult rats, involving peripheral and central mechanisms (Lewin et al, 1993(Lewin et al, , 1994. The latter may include an enhanced release of SP within the dorsal horn of the spinal cord, which we have recently demonstrated to occur after prolonged treatment with NGF (Malcangio et al, 1997).…”

Presence of NGF and its receptor TrkA in degenerative lumbar facet joint specimens

“…It increases the sensitivity of highthreshold receptors, so that stimuli of lower intensity than normal can activate them, and NGF is implicated in the regulation of hyperalgesia. In particular, systemic injections of large quantities of NGF into rats cause hypersensitivity to noxious heat and mechanical stimuli that persists for days [10]. Similar observations also were made with humans with lower doses of NGF [11].…”

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

“…In postnatal animals, for example, sequestration of endogenous NGF using anti-NGF antiserum or a TrkA-IgG fusion protein causes loss of nociceptor function (Ritter et al, 1991;Lewin and Mendell, 1994;McMahon et al, 1995;Bennett et al, 1998). Experimentally increasing levels of NGF in the skin, either by administration of exogenous NGF or in transgenic mice selectively overexpressing NGF in skin, enhances the sensitivity of nociceptors to noxious stimuli (Lewin et al, 1993;Lewin and Mendell, 1994;Rueff and Mendell, 1996;. Furthermore, NGF has been shown to be an important mediator of hyperalgesia in inflammatory pain states.…”