PII S0031-9384(98)00055-9 Alterations in Swim Stress-induced Analgesia and Hypothermia Following Serotonergic or NMDA Antagonists in the Rostral Ventromedial Medulla of Rats EILEEN HOPKINS, MARCELLO SPINELLA, ZORAN W. PAVLOVIC AND RICHARD J. BODNAR 1 Neuropsychology Doctoral Subprogram, Queens College, City University of New York, Flushing, NY 11367 Received 30 December 1997; Accepted 12 January 1998 HOPKINS, E., M. SPINELLA, Z. W. PAVLOVIC AND R. J. BODNAR. Alterations in swim stress-induced analgesia and hypothermia following serotonergic or NMDA antagonists in the rostral ventromedial medulla of rats. PHYSIOL. BEHAV. 64(3) 219 –225, 1998.—Serotonergic, NMDA, or opioid antagonists in the rostral ventromedial medulla (RVM) reduce morphine analgesia elicited from the periaqueductal gray (PAG). Continuous (CCWS) and intermittent (ICWS) cold-water swims elicit respective naltrexone-insensitive and naltrexone-sensitive analgesic responses. CCWS analgesia is reduced by systemic NMDA receptor antagonism and by systemic, but not intrathecal serotonergic antagonism. ICWS analgesia is reduced by both systemic and intrathecal serotonergic antagonism, but unaffected by systemic NMDA antagonism. The present study evaluated whether serotonergic (methy- sergide: 5–10 g) or competitive [AP7 (2-amino-7-phosphonoheptanoic acid): 0.01– 0.1 g] or non-competitive [MK-801 (dizocilipine maleate): 0.3–3 g] NMDA antagonists in the RVM altered CCWS and ICWS analgesia and hypothermia as well as basal nociceptive latencies. Methysergide in the RVM significantly potentiated CCWS, but not ICWS analgesia. In contrast, AP7 in the RVM significantly potentiated ICWS analgesia. Antagonist-induced changes in either hypothermia or basal nociception failed to account for any alterations in stress-induced analgesia. These data suggest that serotonergic, but not NMDA, receptors in the RVM may mediate collateral inhibition between mesencephalic morphine analgesia and naltrexone-insensitive CCWS analgesia. © 1998 Elsevier Science Inc. Analgesia Hypothermia Stress Rostral ventromedial medulla AP7 MK-801 Methysergide Continuous cold-water swims Intermittent cold-water swims ANALGESIC responses to stress have been typically character- ized primarily in terms of their mediation by opioid and nonopioid mechanisms of action (see References 2,25,36,43). One important and intriguing finding is that these opioid or nonopioid analgesic mechanisms can be activated by specific parameters of given stressors such as forced swims (3,4,7,11,12,26,35). In this regard, analgesia elicited by intermittent cold-water swims (ICWS: 2°C, eighteen 10-s swims and recoveries) is cross-tolerant with mor- phine analgesia and blocked by naloxone pretreatment in rats (11,12), whereas analgesia elicited by continuous cold-water swims (CCWS: 2°C for 3 min) is insensitive to these treatments (3,4). There have been many instances in which given manipula- tions alter opioid-mediated and nonopioid-mediated analgesic re- sponses in opposite ways. Our laboratory (2) has proposed a collateral inhibition model to explain interactions between opioid- mediated and nonopioid-mediated pain-inhibitory systems. Their very existence suggests that these two (or more) systems respond differentially or specifically to incoming environmental stimuli, rather than the potentially maladaptive circumstance of immediate and equal activation in response to any nociceptive stimulus. This model would predict a parsimonious hierarchy of analgesic re- sponses with less appropriate systems held in reserve. Thus, acti- vation of one pain-inhibitory system (A) by endogenous or exog- enous stimuli should produce its analgesic response, but should also inhibit the activity of a second system (B) with the magnitude of the effect dependent upon each system’s tonic activational state and the magnitude of the activational stimuli. If the A system acts through the endogenous opioids, then it should be enhanced and reduced by respectively increasing and decreasing the activity of the endogenous opioid system. Concurrently, B analgesia would be modulated by endogenous opioid activity in an opposite man- ner. Hence, endopeptidase (anti-enkephalinase) inhibitors potenti- ate ICWS (A) analgesia (15), but reduce CCWS (B) analgesia (6). Moreover, CCWS (B) analgesia is potentiated by either chronic naltrexone pretreatment (46) or  1 -opioid receptor antagonism (21). Indeed, if morphine (A) and CCWS (B) are applied simulta- 1 To whom requests for reprints should be addressed. E-mail: rjb$psy@qc1.qc.edu Physiology & Behavior, Vol. 64, No. 3, pp. 219 –225, 1998 © 1998 Elsevier Science Inc. All rights reserved. Printed in the U.S.A. 0031-9384/98 $19.00 + .00 219