Neurokinin-l receptor and CL-opioid receptor agonists affect respiratory rh
ythm when injected directly into the preBotzinger brainstem complex, which
is the hypothesized site for respiratory rhythmogenesis in mammals (Science
286 (1999) 1566). Early stress-induced analgesia (SIA) is naloxone-insensi
tive and as such considered independent of the activation of the mu -opioid
system. Prolonged application of electrical shocks, however, produces anal
gesia that is mediated by the Cc-opioid system (Science 208 (1980) 623). To
gether these findings suggest that any early pain-specific increased respir
ation should be attenuated in the tonic state of pain. Ten healthy, pain-fr
ee female volunteer subjects participated in this experimental study involv
ing deep acute and tonic pain. The experimental design included three condi
tions: (1) baseline; (2) pain; and (3) a placebo control stimulus. Experime
ntal pain was induced by the infusion of hypertonic saline into the massete
r muscle. Infusion of isotonic saline in the contralateral masseter was use
d as a control. Blinded subjects were randomly assigned to a particular seq
uential order of the experimental stages, i.e. hypertonic saline infusion p
receded the isotonic saline infusion or vice versa. Respiration rate, mean
peak inspiratory and expiratory how rates, and the minute ventilation volum
e quantified breathing. Results indicate that effects on respiration were p
ain-specific and that the early effects on respiration were significantly a
ttenuated in sustained pain. In the early stage of pain, all monitored vari
ables (respiration rate, minute Ventilation volume, and inspiratory and exp
iratory flow rates) were elevated to statistically significant degrees when
compared to measurements taken at baseline or during control infusion. Onl
y respiration rate continued to be significantly elevated in sustained pain
. We concluded that rhythmogenic neurons in the preBotzinger brainstem comp
lex appear as the likely target for pro-nociceptive and anti-nociceptive in
put, explaining both the observed initial facilitation and subsequent habit
uation of respiration in early and sustained pain. (C) 2001 International A
ssociation for the Study of Pain. Published by Elsevier Science B.V. All ri
ghts reserved.