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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.

Peripheral nerve injury leads to substantial alterations in injured sensory neurons. These include cell death, phenotypic modifications, and regeneration. Primary sensory neurons have recently been shown not to die until a time beyond 4 months following a nerve crush or ligation and this loss is, moreover, limited to cells with unmyelinated axons, the C-fibers. The late loss of C-fibers may be due to a lack of target reinnervation during the regenerative phase. In order to investigate this, we have used a particular peripheral function, unique to C-fibers, as a measure of peripheral reinnervation: an increase in capillary permeability on antidromic activation of C-fibers, i.e., neurogenic extravasation. This was investigated in rats that had received a nerve crush injury 1 to 50 weeks earlier. Some recovery of the capacity of C-fibers to generate extravasation was detected at 8–10 weeks, which increased further at 12–14 weeks, and then plateaued at this level with no further recovery at 30 or 50 weeks. In intact and damaged sciatic nerves, Aβ-fibers never induced extravasation. These findings are compatible with the hypothesis that those C-fibers which make it back to their peripheral targets do not subsequently die and those that do not, may die.

Behavioral analysis of the NK1 receptor gene knock-out (NK1-/-) mouse indicated that substance P was closely involved in orchestrating the physiological and behavioral response of the animal to major environmental stressors. In particular, endogenous pain control mechanisms, such as stress-induced analgesia were substantially impaired in mutant mice, suggesting a reduction in descending inhibitory controls to the spinal cord from the brainstem. To directly test the integrity of descending controls in NK1-/- mice, we have analyzed c-Fos expression in laminae I-II of the lumbar and cervical cord and in the rostral ventromedial medulla in an experimental paradigm known to require recruitment of descending inhibitory controls. Anesthetized mice were stimulated with water at 50 degrees C either on their forepaw, hindpaw, or on both the hindpaw plus forepaw concurrently. Wild-type mice, naive or treated with an NK1 antagonist (RP67580) or its inactive isomer (RP68651), were compared with NK1-/- mice. C-Fos expression at the lumbar laminae I-II level was significantly reduced, whereas it was significantly greater in the raphe magnus and pallidus nuclei in the double stimulation situation in wild-type compared with NK1-/- mice. Blocking the NK1 receptor pharmacologically reproduced, in an enantiomere-selective manner, the data from NK1-/- mice, with no evidence for recruitment of descending inhibition at the lumbar cord level after forepaw stimulation. The present study demonstrates that the NK1 receptor is essential for the full development of noxiously evoked descending inhibition.