Hypoxia attenuates the respiratory response to injection of substance P into the nucleus of the solitary tract of the rat Stuart B. Mazzone a , Colin F. Hinrichsen b , Dominic P. Geraghty a, * a School of Biomedical Science, University of Tasmania, Launceston, Tasmania 7250, Australia b Discipline of Anatomy and Physiology, University of Tasmania at Hobart, Tasmania 7001, Australia Received 20 July 1998; received in revised form 17 August 1998; accepted 1 September 1998 Abstract Prolonged or repetitive bouts of hypoxia may desensitize the brain stem respiratory centres leading to reduced stimulation of ventilation. We investigated the possible involvement of changes in the sensitivity of the commissural nucleus of the solitary tract (cNTS) to the tachykinin peptide, substance P (SP). Urethane-anaesthetised rats were allowed to breath room air (normoxic) or subjected to four, 30 s bouts of hypoxia (10% O 2 /90% N 2 ) prior to the injection of SP (750 pmol) into the cNTS. In normoxic rats (n = 5), SP produced a fall in frequency (f, 88 ± 4% control) after 4 min and a maximum rise in tidal volume (V T ) after 6 min (138 ± 10% control) leading to an overall increase in minute ventilation (V E , maximum, 127 ± 12% control after 2 min). In rats (n = 5) exposed to four bouts of hypoxia and allowed to recover for 10 min, injection of SP produced a similar fall in f but a delayed and significantly (P  0.001) reduced V T (maximum after 10 min, 110 ± 1% control) and hence, V E response (104 ± 3% control). Sixty min after hypoxia, the f, V T and V E responses to SP were identical to those of normoxic rats. These data suggest that hypoxia desensitizes SP receptors in the cNTS and this may partly explain why the respiratory response to hypoxia declines over time.  1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Substance P; Hypoxia; Nucleus of the solitary tract; Respiration The tachykinin substance P (SP) appears to be a key neurotransmitter of the peripheral chemoreceptor reflex. SP-containing afferent projections from carotid body che- moreceptors travel in the carotid sinus nerve and terminate in a number of regions of the nucleus of the solitary tract (NTS), including the commissural subnucleus (cNTS), and nearby dorsal motor nucleus of the vagus nerve [2,4,6,10,17]. Moreover, SP levels in the NTS are substan- tially elevated following hypoxic activation of the carotid body chemoreceptors [1,11]. Pharmacological studies also support a role for SP in chemoreceptor integration. Intracer- ebroventricular (i.c.v.), and microinjection of SP into var- ious brain stem sites, stimulates ventilation, while injection of SP receptor (neurokinin-1; NK1) antagonists block these facilitatory effects [3,5]. The mammalian respiratory response to hypoxia (RRH) is distinctly biphasic [7,12]. Both neonates and adults initi- ally respond to hypoxia by hyperventilating (an increase in minute ventilation). However, if hypoxia is prolonged, hyperventilation gradually declines in the adult and may actually revert to hypoventilation in the neonate. The mechanisms underlying the biphasic RRH are not fully understood although failure to maintain hyperventilation during hypoxia has been linked to sudden infant death syn- drome (SIDS). We have previously demonstrated that both single and multiple acute (5 min) bouts of hypoxia (8.5% O 2 in N 2 ) deplete the number of SP (NK1) receptors in key brain stem nuclei (including the NTS) involved in chemoreceptor reflex control of ventilation [15]. In the NTS, receptor depletion appears to be dynamic, reaching a maximum 5 min after hypoxia but returning to prehypoxic levels within 60 min. Presumably, this reduction in receptor numbers would attenuate the hyperventilatory effects of SP. Several Neuroscience Letters 256 (1998) 9–12 0304-3940/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(98)00743-5 * Corresponding author. P.O. Box 1214. Tel.: +61 3 63243379; fax: +61 3 63243658; e-mail: d.geraghty@utas.edu.au