Transient attenuation of CO₂ sensitivity after neurotoxic lesions in the medullary raphe area of awake goats

Abstract

. Transient attenuation of CO 2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats. J Appl Physiol 97: 2236 -2247, 2004. First published August 20, 2004; doi:10.1152/japplphysiol.00584.2004The major objective of this study was to gain insight into whether under physiological conditions medullary raphe area neurons influence breathing through CO 2/H ϩ chemoreceptors and/or through a postulated, nonchemoreceptor modulatory influence. Microtubules were chronically implanted into the raphe of adult goats (n ϭ 13), and breathing at rest (awake and asleep), breathing during exercise, as well as CO 2 sensitivity were assessed repeatedly before and after sequential injections of the neurotoxins saporin conjugated to substance P [SP-SAP; neurokinin-1 receptor (NK1R) specific] and ibotenic acid (IA; nonspecific glutamate receptor excitotoxin). In all goats, microtubule implantation alone resulted in altered breathing periods, manifested as central or obstructive apneas, and fractionated breathing. The frequency and characteristics of the altered breathing periods were not subsequently affected by injections of the neurotoxins (P Ͼ 0.05). Three to seven days after SP-SAP or subsequent IA injection, CO 2 sensitivity was reduced (P Ͻ 0.05) by 23.8 and 26.8%, respectively, but CO 2 sensitivity returned to preinjection control values Ͼ7 days postinjection. However, there was no hypoventilation at rest (awake, non-rapid eye movement sleep, or rapid eye movement sleep) or during exercise after these injections (P Ͼ 0.05). The neurotoxin injections resulted in neuronal death greater than three times that with microtubule implantation alone and reduced (P Ͻ 0.05) both tryptophan hydroxylase-expressing (36%) and NK1R-expressing (35%) neurons at the site of injection. We conclude that both NK1R-and glutamate receptor-expressing neurons in the medullary raphe nuclei influence CO 2 sensitivity apparently through CO 2/H-expressing chemoreception, but the altered breathing periods appear unrelated to CO 2 chemoreception and thus are likely due to non-chemoreceptor-related neuromodulation of ventilatory control mechanisms. central chemoreception; control of breathing THE MEDULLARY RAPHE NUCLEI project to and supposedly modulate several central nervous system regions, including the pre-Bötzinger complex; the hypoglossal, phrenic, and spinal motoneurons; the nucleus ambiguus; the nucleus of the solitary tract; and various pontine nuclei (3,4,8,16,(37)(38)(39). The neuronal population in the raphe is heterogeneous, containing neurokinin-1 receptor-expressing (NK1R) and serotonergic neurons (28). Serotonergic neurons corelease thyrotropin-releasing hormone and substance P (SP), which are all capable of modulating ventilation (5, 7, 14, 15, 19 -21). Therefore, these raphe neurons are capable of influencing breathing through multiple neuromodulators acting at multiple levels, including the rhythm-and pattern-generating neurons and motoneurons. The primary site of raphe neuromodulation during physiological condition...

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

“…Raphé lesions in adult goats induce central apnea in vivo (Hodges et al, 2004b). In addition, Pet1 null mice with a 70% decrease in number of 5-HT neurons exhibit greater variability of respiratory output during the neonatal period (Erickson et al, 2007).…”

Preventive Effect of Fastigial Nucleus on Oxidative Damage in Rats Undergoing Acute Myocardial Infarction

“…8,9) FNL by injection of the neurotoxin ibotenic acid conferred dramatic effects on posture and locomotion. To demonstrate that the neuronal bodies in the FN areas injected with ibotenic acid were effectively destroyed, we did a comparison.…”

Ventilatory effects of substance P-saporin lesions in the nucleus tractus solitarii of chronically hypoxic rats

“…The fact that NK1R cell destruction in the NTS does not diminish the HCVR in normoxia was unexpected. Lesions of the NK1R cells in both the RTN and medullary raphe, which are other sites of CO 2 sensitivity, have been shown to decrease the HCVR (20,41,45). While the role of the NK1R cells in central CO 2 sensitivity is unknown, the NK1R is present in every site of central chemosensitivity (37).…”

“…We were surprised that NK1R lesion in the caudal NTS produced no effect on the HCVR in N control animals, in contrast to similar lesions in the RTN or raphe (20,45,46). Like other areas of central CO 2 sensitivity, the NTS can clearly contribute to a central CO 2 -sensitive ventilatory response (38), but, unlike other areas, it is not necessary for a normal ventilatory response to CO 2 in intact animals.…”

“…All of the putative central chemoreceptor areas contain cells expressing the NK1R, which is the receptor for substance P (SP) (37). The role of NK1R cells in CO 2 sensitivity is not known, but lesions specifically targeting the NK1R cells in other chemosensitive areas of the brain stem decrease the hypercapnic ventilatory response (HCVR) in rats and goats (20,45,46). Moreover, it has been shown that NK1R cell lesions in the NTS do not kill the animal (52).…”