Neurokinin-1 receptor and mu-opioid receptor agonists affect respiratory rhythm when injected directly into the preBötzinger brainstem complex, which is the hypothesized site for respiratory rhythmogenesis in mammals (Science 286 (1999) 1566). Early stress-induced analgesia (SIA) is naloxone-insensitive and as such considered independent of the activation of the mu-opioid system. Prolonged application of electrical shocks, however, produces analgesia that is mediated by the mu-opioid system (Science 208 (1980) 623). Together these findings suggest that any early pain-specific increased respiration should be attenuated in the tonic state of pain. Ten healthy, pain-free female volunteer subjects participated in this experimental study involving deep acute and tonic pain. The experimental design included three conditions: (1) baseline; (2) pain; and (3) a placebo control stimulus. Experimental pain was induced by the infusion of hypertonic saline into the masseter muscle. Infusion of isotonic saline in the contralateral masseter was used as a control. Blinded subjects were randomly assigned to a particular sequential order of the experimental stages, i.e. hypertonic saline infusion preceded the isotonic saline infusion or vice versa. Respiration rate, mean peak inspiratory and expiratory flow rates, and the minute ventilation volume quantified breathing. Results indicate that effects on respiration were pain-specific and that the early effects on respiration were significantly attenuated in sustained pain. In the early stage of pain, all monitored variables (respiration rate, minute ventilation volume, and inspiratory and expiratory flow rates) were elevated to statistically significant degrees when compared to measurements taken at baseline or during control infusion. Only respiration rate continued to be significantly elevated in sustained pain. We concluded that rhythmogenic neurons in the preBötzinger brainstem complex appear as the likely target for pro-nociceptive and anti-nociceptive input, explaining both the observed initial facilitation and subsequent habituation of respiration in early and sustained pain.