Portions of the brain stem seem normally to inhibit pain. In man and laboratory animals these brain areas and pathways from them to spinal sensory circuits can be activated by focal stimulation. Endogenous opioids appear to be implicated although separate nonopioid mechanisms are also evident. Stress seems to be a natural stimulus triggering pain suppression. Properties of electric footshock have been shown to determine the opioid or nonopioid basis of stress-induced analgesia. Two different opioid systems can be activated by different footshock paradigms. This dissection of stress analgesia has begun to integrate divergent findings concerning pain inhibition and also to account for some of the variance that has obscured the reliable measurement of the effects of stress on tumor growth and immune function.

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Inescapable foot shock in rats caused profound analgesia that was antagonized by naloxone or dexamethasone when shock was delivered intermittently for 30 minutes, but not when it was delivered continuously for 3 minutes. Thus, depending only on its temporal characteristics, foot-shock stress appears to activate opioid or nonopioid analgesia mechanisms. Certain forms of stress may act as natural inputs to an endogenous opiate analgesia system.

Opioid and non-opioid mechanisms of analgesia elicited by two kinds of footshock stress that differ only in temporal characteristics previously have been inferred on the basis of susceptibility to naloxone blockade. The present study sought further evidence on this point by comparing these two kinds of footshock analgesia for possible tolerance development and cross-tolerance with morphine. It was found that, with repeated exposure to stress, tolerance developed to naloxone-sensitive, but not naloxone-insensitive, stress analgesia. Furthermore, morphine-tolerant rats displayed cross-tolerance to only the naloxone-sensitive form of footshock analgesia. Although prior exposure to both footshock paradigms potentiated morphine analgesia, less potentiation occurred in rats tolerant to the naloxone-sensitive footshock stress. Thus, cross-tolerance between morphine and this type of stress analgesia appears to occur in both directions. These findings are consistent with those using naloxone antagonism as a criterion for opioid mediation and support the conclusion that separate opioid and non-opioid mechanisms of stress analgesia exist.

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A study of 13 male opiate addicts was undertaken to investigate the feasibility of transferring abruptly from methadone maintenance treatment to buprenorphine in an outpatient setting. The mean age of subjects was 30 years (range 18-45) and all fulfilled DSM-III-R criteria for opioid dependence. All were maintained on a methadone dose of 20-30 mg mixture daily and were transferred for 3 days to 4 mg buprenorphine sublingually 24-26 hours after their last dose of methadone. On day 1 repeated measures of drug effects were performed, including agonist and withdrawal effects, and this was complemented by saccadic eye movements, a potential new measure of central opioid effects. These recordings were repeated once on days 2 and 3 and the subjects returned to their previous dose of methadone on day 4. Buprenorphine caused no detectable agonist effects or drug "high", but had "good" effects, was "liked" and well tolerated, suggesting that subjects would comply with buprenorphine treatment despite the lack of reinforcing effects. A mild increase in subjective withdrawal symptoms, which was not clinically significant, was seen in association with an increase in saccadic peak velocity on day 2 of the study but no withdrawal occurred on the other days, indicating that the abrupt transfer technique was acceptable.

Opioid peptides appear to be important neurochemical mediators in central nervous system mechanisms of analgesia, cardiovascular control, and many endocrinological responses to stress. The nucleus tractus solitarius (NTS), a brain region expressing all 3 opioid peptide families, is also associated with regulation of autonomic and endocrine functions. We now report that electrical stimulation of the NTS causes pronounced analgesia in rats. This analgesia appears to involve opioids and is pharmacologically dissociable from the hemodynamic changes elicited by NTS stimulation. These results suggest the NTS as a neural substrate for inter-relationships between stress, cardiovascular function, alterations in respiration, and pain sensitivity.