Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat

Abstract

We have investigated the co-involvement of endogenous NGF and impulses in the collateral sprouting of cutaneous sensory nerves in adult rats, specifically the A delta-axons involved in mechanonociception and the C-fibers that mediate heat nociception. Their collateral sprouting was measured by the progressive expansion, respectively, of the behaviorally defined "pinch" and "heat" fields into surrounding denervated skin (the light-touch A alpha-fibers do not sprout in adult mammals). The expansions of such "isolated" fields were totally prevented in animals injected daily with anti-NGF serum, but developed normally after treatment was discontinued. Light microscopic and EM examination of the skin confirmed that the effect of the anti-NGF treatment was attributable to its prevention of collateral sprouting. Initiation of treatment would also rapidly halt sprouting already in progress. Finally, intradermal injections of purified NGF protein would not only increase the rate of nociceptive fiber sprouting, but also evoke sprouting de novo within normally innervated skin (again, A alpha-axons were unaffected). We conclude that the collateral sprouting of intact nociceptive nerves following partial denervation of skin is entirely dependent on endogenous NGF. The observed latency of this sprouting was 10-12 d; we estimate, however, that at least 2 d of field expansion is required for its reliable detection. Thus, about 8-10 d are required for NGF levels in the skin to rise to effective levels, and for the neurons to respond and initiate sprouting. From indirect findings, the NGF component of this sprouting latency appears to be about 2 d. In accord with earlier findings, the remaining "initiation time" was reduced by 5-6 d if the neurons were briefly excited, even 2 d prior to the isolation of their fields. Unexpectedly, this phenomenon of "precocious sprouting" requires that endogenous NGF be available; the sprouting latency reverted to normal values when the conditioning impulses were evoked during a 2 d anti-NGF "umbrella." In contrast to the impulse-sensitive neuronal mechanisms involved in the initiation of sprouting, those underlying the sprouting rate were unaffected by nerve activity and were entirely dependent on the level of endogenous NGF. We suggest that interactions like that revealed in these studies between a sprouting agent and impulses that seem to prime the neuron's response to it contribute to plasticity within the nervous system.

Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis

“…Sympathetic fibres may play a role, as sympathpsychotherapy have all been tried. More recently, capsaicin has been used with some benefit in these etic agents increase NGF secretion from cultured smooth muscle cells, and increased NGF levels, in turn, induce women [17], although the response is inconsistent (with acute exacerbation of pain in some cases), and nerve-fibre sprouting [28]. Further studies are needed to establish whether these mechanisms affect NGF the clinical application of intravesical instillation in its present form is impractical.…”

Peripheral Pathways Regulate Motoneuron Collateral Dynamics

“…The expression of both NGF and BDNF is upregulated by a factor of 30 in denervated cutaneous nerve but barely at all in denervated ventral root (Hoke et al, 2004). These factors not only promote sprouting from sensory (Diamond et al, 1992;Gallo and Letourneau, 1998) and retinal ganglion (Cohen-Corey and Fraser, 1995;Lom and Cohen-Corey, 1999) neurons, but their antibodies reduce sprouting from motoneurons (Streppel et al, 2002). The substantial increase in collateralization within cutaneous nerve may thus result from increased sprouting rather than decreased pruning, an adaptation that could promote eventual pathfinding success.…”

The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain

“…However, the role of NGF in chronic pain remains controversial. On one hand, NGF exerts neuroprotective and trophic action on peptidergic small-diameter dorsal root ganglia cells, reversing many of the histological changes after nerve injury (4,22), and regulates the collateral sprouting of intact nociceptive sensory axons after denervation (23). On the other hand, peripheral neuropathic pain is correlated with elevated NGF levels (24,25), and direct administration of NGF into the sciatic nerve produces hyperalgesia (26) Moreover, NGF function inhibition results in analgesia in different neuropathy-related pain protocols, such as chronic constriction injury and partial sciatic nerve transection (27,28).…”