Early angiogenesis is a key step in the transition from acute to persistent inflammation. The nervous system has long been known to play a role in inflammation, in part through the release of substance P from peripheral nerve terminals (neurogenic inflammation). Application of substance P can stimulate vessel growth in a variety of angiogenesis assays, although it was previously not known whether endogenous substance P released from sensory nerves could modulate angiogenesis. We hypothesized that endogenous substance P can initiate angiogenesis during acute neurogenic inflammation. Here we show that 10 nmol of substance P can stimulate angiogenesis within the rat knee synovium, as shown by increased endothelial cell proliferation index [PCNA index, 19% (95% confidence interval (CI), 17 to 20%)] compared with saline injected knees [6% (95% CI, 4% to 8%), p Ͻ 0.05]. Moreover, this was prevented by coadministration of an antagonist of the neurokinin-1 (NK 1 ) subtype of neurokinin receptor SR140333 (nolpitantium), 1 mol [8% (95% CI, 5% to 11%)]. Capsaicin 0.5%, which stimulates release of endogenous substance P from sensory nerves, was also found to enhance synovial angiogenesis, [PCNA index 17% (95% CI, 14% to 19%)] compared with saline injected control knees [2% (95% CI, 1% to 3%), p Ͻ 0.05], and this also was inhibited by 1 mol of SR140333 [11% (95% CI, 8 to 16%)]. Inhibition of capsaicin-enhanced angiogenesis was incomplete, and this may indicate a contribution of other neuropeptides, in addition to substance P-NK 1 receptor interactions, in capsaicin-enhanced angiogenesis. NK 1 receptor antagonists could have therapeutic potential in conditions where neurogenic angiogenesis contributes to disease.

We sought to characterise the contribution of the neuropeptide substance P to the outcome of two models of footpad inflammation of differing severity. In an intense inflammatory model produced by intra-plantar Mycobacterium tuberculosus (10 mg/ml) substantial reductions in footpad swelling, histological outcome and mechanical hyperalgesia were observed from early time points in mice lacking the neurokin-1 receptor for substance P compared with wild-type controls. Conversely, in a less intense model (M. tuberculosus 1 mg/ml) no differences were observed other than for a reduction in mechanical hyperalgesia at later time points (day 9 onwards). The results point to a previously unrecognised influence of substance P on peripheral tissue injury and the maintenance of hyperalgesia during more severe or more chronic phases of inflammatory disease.

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1. We have studied the characteristics of the abnormal properties of damaged myelinated fibers (conduction velocity > 2.0 m/ s) after peripheral nerve injury in a novel in vitro model of the rat sciatic nerve/dorsal root ganglion/dorsal root (L4-5) preparation removed from control naíve or sham-operated rats and animals that had received sciatic neurectomy 12-24 days before the in vitro study. A total of 122-245 filaments were recorded in each dorsal root. The proportion of A alpha, beta and A delta fibers were not significantly different between control, sham-operated, and axotomized nerves. Spontaneous activity was recorded in 3.4% (A alpha, beta) and 4.6% (A delta) of fibers in comparison with 0.4% (A alpha, beta) and 0.3% (A delta) in naíve controls. 2. A sporadic, irregular, low-frequency (< 1 Hz) firing was seen in 26% of the fibers with spontaneous activity. Periodical (irregular) bursting pattern was observed in 43% of spontaneously active fibers, whereas a relatively stable, ongoing firing pattern (median frequency: 7.1 Hz) was displayed by 31% of active fibers. 3. Mechanosensitivity of the neuroma/peripheral nerve was displayed in preparations from lesioned [axotomized: 18.2% (A alpha, beta) and 14.1% (A delta), sham operated: 2% (A alpha, beta) and 0% (A delta)], but not control naíve animals. There was no correlation between the presence of spontaneous activity and mechanosensitivity in single fibers. 4. The principal site of spontaneous activity generation was the dorsal root ganglion. Transection of the peripheral nerve (or removal of the neuroma), while recording from dorsal root filaments, produced a cessation of firing in 21% of fibers firing with ongoing discharge. The remaining active fibers continued firing until the DRG was removed. A sustained injury discharge was observed in damaged fibers but not control, undamaged fibers from naíve animals after acute peripheral nerve transection. 5. We present an in vitro model for the study of abnormal primary sensory activity in peripheral neuropathy. Although our data are consistent with in vivo electrophysiological findings in published reports, the proportion of damaged afferent fibers displaying spontaneous activity was significantly lower under in vitro conditions. This model may serve as a valuable tool for further physiological and pharmacological studies of peripheral neuropathy.

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