Since von Euler and Gaddum first described substance P (SP) more than 60 years ago1, much evidence has accumulated to suggest that this undecapeptide is released from the terminals of certain sensory nerves, as a chemical neurotransmitter or modulator2. The sensory function of SP is thought, from more circumstantial evidence, to be related to the transmission of pain information into the central nervous system (CNS)2,3. This idea is now supported by two studies reported by Cao et al.4 and De Felipe et al.5 on pages 390 and 394, respectively, of this issue. Both groups find that when the function of SP is genetically disrupted in mice, the animals show reduced responses to painful stimuli.
Cao et al.4 studied mice in which the preprotachykinin A gene was disrupted. This gene encodes the precursor from which both SP and the closely related neuropeptide neurokinin A (NKA) are made. As expected, the mice lacked any detectable SP or NKA, although their development, ability to reproduce and behaviour were unaffected. The animals also showed normal thresholds for reactions to various painful stimuli, such as heat, mechanical pressure or chemical irritants. But when the intensity of the painful stimulus was increased, the knockout mice showed blunted responses, evidenced by increased latencies in the response to the stimulus. The importance of SP/NKA seemed to apply only to a certain ‘window’ of pain intensities — when the intensity of the pain stimulus was further increased, the responses of the knockout animals did not differ much from those of the wild-type mice.
De Felipe et al.5 studied a strain of mouse that lacked the neurokinin-1 (NK-1) receptor, with which SP interacts. These animals resembled those studied by Cao and colleagues in several respects: they did not show any changes in acute pain thresholds in mechanical, electrical or noxious heat tests, but their responses were blunted in tests that involved more intense noxious stimuli. When sensory nerves are subjected to an intense period of noxious stimulation, normal animals show a ‘wind-up’ phenomenon, whereby spinal reflexes are temporarily increased. This is thought to reflect the sensitization of CNS mechanisms by intense noxious stimulation. But such a wind-up was completely absent in the NK-1-receptor knockout mice.
As well as acting in the CNS, SP and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibres in the skin, muscle and joints. This release is thought to be involved in ‘neurogenic inflammation’ — a local inflammatory response to certain types of injury or infection6. But the authors found that this process was impaired in both types of knockout animal. Moreover, the response to capsaicin was also absent or considerably reduced in the knockout mice. Normally, when this irritant is administered to the skin of the ear, it evokes a local oedema (accumulation of fluid) by provoking a release of sensory neuropeptides7.
Similar impairments of the neurogenic inflammatory response to capsaicin and the inflammatory response in the lung after administering an immune complex have already been reported in NK-1-receptor knockout mice by Bozic et al.8. On the other hand, the knockout animals studied by Cao et al. and De Felipe et al. responded normally to an inflammatory stimulus that did not involve a neurogenic component (the injection of complete Freund's adjuvant into a hind paw). Both the local inflammation and the delayed development of heightened pain sensitivity after these injections were unimpaired.
These new data come at an important time. Several pharmaceutical companies are developing drugs that act as potent antagonists of NK-1 receptors, although early results with such agents in animal tests of pain have often proved difficult to interpret. This is partly because the functional roles of SP and the NK-1 receptor are complex, and partly because some of the initial SP antagonists could not adequately penetrate the CNS or had other pharmacological activities that confused the results9. Nevertheless, the results with NK-1 antagonists mirror the present findings quite well — the drugs do not alter acute pain thresholds, but they do affect responses that involve more intense noxious stimulation. For example, they block the wind-up of spinal reflexes9,11.
The results with the knockout mice and with the new SP antagonists show that SP is only one of the many complex mechanisms involved in pain perception. Mild and severe forms of pain involve other neurochemical mechanisms, among which L-glutamate is clearly important12. De Felipe et al.5 also report that, in the NK-1-receptor knockout mice, the analgesic response to cold-water swim stress was considerably impaired. Moreover, these animals were much more aggressive than wild-type mice. The authors conclude “⃛that SP is important for orchestrating the response of the animal to major stressors such as pain, injury or invasion of territory”. If they are right, then SP-receptor antagonists may have broad therapeutic applications in the treatment of a variety of stress-related illnesses, in addition to their potential as analgesics.
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Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography
Nature Communications (2019)
Experimental Brain Research (2009)
Molecular Pain (2005)