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

The major objective of this study was to gain insight into whether under physiological conditions medullary raphe area neurons influence breathing through CO2/H+ chemoreceptors and/or through a postulated, nonchemoreceptor modulatory influence. Microtubules were chronically implanted into the raphe of adult goats (n = 13), and breathing at rest ( awake and asleep), breathing during exercise, as well as CO2 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 > 0.05). Three to seven days after SP-SAP or subsequent IA injection, CO2 sensitivity was reduced ( P < 0.05) by 23.8 and 26.8%, respectively, but CO2 sensitivity returned to preinjection control values >7 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 > 0.05). The neurotoxin injections resulted in neuronal death greater than three times that with microtubule implantation alone and reduced ( P < 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 CO2 sensitivity apparently through CO2/H-expressing chemoreception, but the altered breathing periods appear unrelated to CO2 chemoreception and thus are likely due to non-chemoreceptor-related neuromodulation of ventilatory control mechanisms.