The Journal of Neurophysiology Vol. 88 No. 1 July 2002, pp. 206-213
Copyright ©2002 by the American Physiological Society

Long-Term Deprivation of Substance P in PPT-A Mutant Mice Alters the Anoxic Response of the Isolated Respiratory Network

 ¹Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208;  ²Department of Anatomy, University of California. San Francisco, California 94143-0452; and  ³Department of Organismal Biology and Anatomy, University of Chicago, Chicago, Illinois 60637

Telgkamp, Petra, Yuqing Q. Cao, Allan I. Basbaum, and Jan-Marino Ramirez. Long-Term Deprivation of Substance P in PPT-A Mutant Mice Alters the Anoxic Response of the Isolated Respiratory Network. J. Neurophysiol. 88: 206-213, 2002. The aim of this study was to elucidate the role of the neuromodulator substance P and its related tachykinin neurokinin A (NKA) in the homeostasis of respiratory activity. Respiratory activities, in form of fictive eupneic and sigh activities, were recorded extracellularly from the preBötzinger complex (PBC) in normoxic and anoxic conditions using medullary slice preparations. The effect of a blockade of endogenous substance P was assessed by an acute pharmacological blockade of the receptors with spantide in wild-type animals and by the use of preprotachykinin-A (PPT-A) mutants. These mutants lack from birth the PPT-A gene, which codes for the precursor of substance P and NKA. Spantide treatment reduced frequency (37%, n = 9) and regularity (twofold) of eupneic-like respiratory activity under normoxic conditions, whereas in PPT-A mutants, eupneic-like activity was under normoxic conditions not significantly different from the wild-type mice (WT). The response to short anoxic episodes (5 min) was characterized in the WT by an increase in respiratory frequencies at the onset of anoxia (ratio anoxic/control frequency = 1.9 ± 0.2, n = 18). This anoxic ratio was unaltered in the presence of spantide (ratio = 2.3 ± 0.4, n = 8) but increased in the mutant (ratio = 4.1, n = 15).

We conclude that endogenously released substance P is important for the maintenance of regular respiratory activity. Short-term blockade of substance P receptors decreases the frequency and regularity of rhythmic activity. Long-term deficiency in substance P leads to compensatory mechanisms that result in an apparently normal respiratory activity under normoxic conditions but a significantly altered response of the respiratory network during anoxia.