Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. I. Characterization.
The effect of intravenous (i.v.) serotonin (5-HT) on nociception and blood pressure was examined in male Sprague-Dawley rats. Intravenous 5-HT produced a dose-dependent (6-192 micrograms/kg, i.v.) inhibition of the nociceptive tail-flick (TF) reflex in lightly pentobarbital-anesthetized (ED50 = 40 micrograms/kg) and conscious rats (ED50 = 44 micrograms/kg). In the lightly pentobarbital-anesthetized rat, the blood pressure response to i.v. 5-HT was typically a triphasic response with a marked Bezold-Jarisch reflex-induced decrease in pressure (associated with a brief period of apnea) followed by a pressor phase and a subsequent delayed hypotension. In the conscious rat, the response was typically biphasic with the late hypotensive phase absent. A variety of anatomical and pharmacological manipulations were performed to characterize the 5-HT-induced inhibition of the TF reflex and associated changes in blood pressure. Prevention of 5-HT-induced reflex apnea by artificial ventilation did not affect inhibition of the TF reflex produced by 5-HT. Pharmacological manipulations were performed to mimic, as closely as possible, the acute increases and decreases in blood pressure associated with i.v. 5-HT. Nitroprusside (8 micrograms/kg, i.v.) produced a decrease in blood pressure of similar magnitude and rate as that associated with the Bezold-Jarisch reflex-induced decrease in pressure produced by 72 micrograms/kg 5-HT, but did not change TF latency from baseline. Similarly, acute increases in pressure produced by phenylephrine (8 micrograms/kg, i.v.), intended to mimic the secondary pressor effect of 5-HT, did not change TF latency. The short-acting ganglion blocker trimethaphan (5 mg/kg, i.v.) closely mimicked the late hypotensive phase produced by 5-HT, but again resulted in no change in TF latency. Pretreatment with the ganglion blocker chlorisondamine (2.5 mg/kg) abolished all depressor responses to 72 micrograms/kg 5-HT, but did not significantly affect the TF reflex. These results indicate that acute changes in blood pressure and respiration associated with i.v. 5-HT do not contribute to inhibition of the TF reflex. This conclusion was confirmed in experiments in which bilateral vagotomy abolished approximately 70% of the 5-HT-induced inhibition of the TF reflex (and all depressor responses), and resulted in a significantly greater pressor response. Finally, low thoracic spinal cord transection (T9-10) abolished the inhibition of the TF reflex produced by i.v. 5-HT. Therefore, 5-HT stimulates vagal afferents and inhibits the TF reflex by activating descending inhibitory systems from the brainstem.(ABSTRACT TRUNCATED AT 400 WORDS)
Meller
S T
ST
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City 52242.
Lewis
S J
SJ
Ness
T J
TJ
Brody
M J
MJ
Gebhart
G F
GF
D000344:Afferent Pathways / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002714:Chlorisondamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D007275:Injections, Intravenous; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012018:Reflex / Q000187:drug effects*; D012121:Respiration, Artificial; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology*; D012867:Skin / Q000294:innervation; D013116:Spinal Cord / Q000502:physiology; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*
D012701:Serotonin; D002714:Chlorisondamine