Behavioral Neuroscience 1993, Vol. 107. No. 3. 493-505 Copyright 1993 by the American Psychological Association, Inc. 0735-7044/93/S3.00 Activation of the Opioid and Nonopioid Hypoalgesic Systems at the Level of the Brainstem and Spinal Cord: Does a Coulometric Relation Predict the Emergence or Form of Environmentally Induced Hypoalgesia? Mary W. Meagher, Ping-Sun Chen, Juan A. Salinas, and James W. Grau Prior research suggests that a coulometric relation (Intensity x Duration) determines whether an opioid or nonopioid hypoalgesic system is activated by afferent nociceptive information. Using a paradigm that generates a brainstem-mediated hypoalgesia on the tail-flick test, we found that a coulometric relation does not predict either the emergence or the form of shock-induced hypoalgesia in decerebrate rats. In fact, no evidence was obtained that the brainstem's opioid hypoalgesic system can be activated by ascending neurons. More severe shocks elicited hypoalgesia in spinalized rats. Although a coulometric relation did not predict the emergence of hypoalgesia in spinalized rats, shock severity did predict the form of the hypoalgesia; the least severe shocks elicited an opioid hypoalgesia, and the more severe shocks generated a nonopioid hypoalgesia. A similar pattern of data was observed in intact rats exposed to the least severe shock parameters. Considerable evidence now exists that neural systems within the brainstem can modulate pain by attenuating the flow of nociceptive information at the level of the spinal cord (Amit & Galina, 1986; Kelly, 1986). Supporting this, researchers have shown that electrical stimulation of brainstem nuclei attenu- ates both spinally mediated (e.g., tail withdrawal from radiant heat [the tail-flick test]; D'Amour & Smith, 1941; Irwin, Houde, Bennett, Hendershot, & Seevers, 1951) and supraspi- nally mediated (e.g., vocalization) measures of pain reactivity (Basbaum, Marley, O'Keefe, & Clanton, 1977; Mayer & Hayes, 1975; Mayer, Wolfe, Akil, Carder, & Liebeskind, 1971; Reynolds, 1969). In addition, such stimulation can also inhibit the firing of cells in the dorsal horn that selectively respond to nociceptive stimuli (Liebeskind, Guilbaud, Besson, & Ol- iveras, 1973; Oliveras, Besson, Guilbaud, & Liebeskind, 1974). Taken together, these findings suggest that brainstem systems can modulate pain by controlling the flow of nociceptive information at the level of the spinal cord (Basbaum & Fields, 1984; Basbaum et al., 1977). Mary W. Meagher, Ping-Sun Chen, Juan A. Salinas, and James W. Grau, Department of Psychology, Texas A&M University. These experiments were conducted in partial fulfillment of the requirements for Mary W. Meagher's doctoral degree at the University of North Carolina. Preparation of this article was supported by grants from the National Science Foundation (BNS 881981) and the National Institute of Mental Health (R01 MH48994-01A1) to James W. Grau and Mary W. Meagher. We would like to thank DuPont Pharmaceuticals for generously providing naltrexone. We would also like to thank Mary W. Meagher's dissertation committee (Linda Dykstra, David A. Eckerman, Richard A. King, William Maixner, Mark E. Stanton, and Meredith J. West) and Paul A. Illich for their helpful comments on an earlier version of this article. Correspondence concerning this article should be addressed to Mary W. Meagher, Department of Psychology, Texas A&M Univer- sity, College Station, Texas 77843. The discovery of endogenous opioids (Cox, Goldstein, & Li, 1976; Goldstein, Tachibana, Lowney, Hunkapiller, & Hood, 1979; Hughes et al., 1975) naturally led researchers to wonder whether stimulation-produced hypoalgesia is opioid mediated. Early studies suggested that the effect is, at least in part, opioid mediated because it is attenuated by both opiate antagonists (e.g., naloxone or naltrexone) and morphine tolerance (Akil, Mayer, & Liebeskind, 1976; Mayer & Hayes, 1975). However, it is clear that a significant hypoalgesia survived these manipu- lations, which suggests that nonopioid mechanisms are also involved. These, and other findings (e.g., Cannon, Lewis, Weinberg, & Liebeskind, 1983; Watkins, Young, Kinscheck, & Mayer, 1983), suggest that opioid and nonopioid hypoalgesic systems exist within the brainstem, both of which can inhibit the flow of nociceptive information at the level of the spinal cord (Basbaum & Fields, 1984; Watkins & Mayer, 1982). Over the last decade, researchers have attempted to delin- eate the environmental conditions that engage these brainstem hypoalgesic systems (e.g., Fanselow, 1984; Grau, Hyson, Maier, Madden, & Barchas, 1981; Grau, 1987a; Lewis, Cannon, & Liebeskind, 1980; Maier, 1989; Terman, Shavit, Lewis, Can- non, & Liebeskind, 1984; Watkins & Mayer, 1982). One intriguing proposal is that the severity of the aversive event determines whether the opioid or nonopioid hypoalgesic system is activated (Fanselow, 1984; Terman et al., 1984). For example, Terman et al. showed that either 3 min of 1.5-mA gridshock or 1 min of 2.5-mA gridshock elicited a naltrexone- sensitive hypoalgesia in both awake and pentobarbital- anesthetized rats on the tail-flick test. Interestingly, when the duration of the 2.5-mA shock was increased, the hypoalgesia became naltrexone insensitive. Similarly, when the intensity of the 3-min shock was increased, the hypoalgesia became naltrex- one insensitive. On the basis of these findings, Terman et al. suggested that a coulometric relation (Intensity x Duration) determines whether the opioid or nonopioid system is en- gaged. According to this hypothesis, low coulometric products 493 This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.