Ž . Brain Research 829 1999 151–159 Research report Actions of NMDA and cholinergic receptor antagonists in the rostral ventromedial medulla upon b-endorphin analgesia elicited from the ventrolateral periaqueductal gray Marcello Spinella, Vladimir Znamensky, Malgorzata Moroz, Andre Ragnauth, Richard J. Bodnar ) Departments of Psychology and Neuropsychology, Doctoral Subprogram, Queens College, City UniÕersity of New York, 65-30 Kissena BlÕd., Flushing, NY 11367, USA Accepted 9 March 1999 Abstract Analgesia elicited by morphine in the ventrolateral periaqueductal gray is mediated in part by NMDA and cholinergic receptors in the rostral ventromedial medulla because selective receptor antagonists applied to the latter structure reduced morphine analgesia elicited from the former structure. Previous studies have demonstrated that morphine and b-endorphin employ different anatomical and neurochemical pathways in exerting their supraspinal analgesic effects. The present study evaluated whether pretreatment with either Ž . Ž . Ž . competitive AP7, 3–10 mg or non-competitive MK-801, 3–10 mg NMDA antagonists, or muscarinic scopolamine, 5 mg or nicotinic Ž . Ž . mecamylamine, 1 mg cholinergic antagonists administered into the rostral ventromedial medulla altered b-endorphin 15 mg analgesia elicited from the ventrolateral periaqueductal gray as measured by the tail-flick and jump tests in rats. Whereas AP7 produced minimal Ž . Ž . Ž . Ž 11% and transient 30 min reductions in b-endorphin analgesia on the jump test, MK-801 produced minimal 9% and transient 30 . min reductions in b-endorphin analgesia on the tail-flick test. Whereas mecamylamine failed to reduce b-endorphin analgesia on either Ž . Ž . measure, scopolamine produced small 23% and transient 30 min reductions in b-endorphin analgesia on the tail-flick test. Each of these antagonists administered into the rostral ventromedial medulla at comparable or lower doses virtually eliminated morphine analgesia elicited from the ventrolateral periaqueductal gray. The opioid mediation of b-endorphin analgesia in the ventrolateral periaqueductal gray Ž . was confirmed by its sensitivity to naltrexone 1–20 mg pretreatment into the same structure. These data provide further evidence for dissociations between the descending neuroanatomical and neurochemical circuitry mediating the supraspinal analgesic responses induced by morphine and b-endorphin, and indicate that the latter response is mediated by either non-cholinergic and non-NMDA synapses within the rostral ventromedial medulla, andror by brainstem sites outside of the rostral ventromedial medulla. q 1999 Elsevier Science B.V. All rights reserved. Keywords: b-Endorphin analgesia; AP7; MK801; NMDA receptor; Scopolamine; Mecamylamine; Cholinergic receptor; Ventrolateral periaqueductal gray; Rostral ventromedial medulla 1. Introduction An integral component of supraspinal mediation of morphine-induced analgesia is the connection between the Ž . midbrain ventrolateral periaqueductal gray vlPAG and Ž . wx rostral ventromedial medulla RVM 3 . Direct vlPAG- w x RVM projections have been described 1,5,61–63 , and analgesic synergy between the vlPAG and RVM has been observed using morphine, m-selective and d -selective ag- 2 w x onists 35,36 . Our laboratory has identified receptor sys- tems within the RVM that mediate morphine analgesia ) Corresponding author. Fax: q1-718-997-5257; E-mail: rjb$psy@qc1.qc.edu elicited from the vlPAG. Thus, serotonergic receptors have been implicated since either general, 5HT or 5HT antag- 2 3 onists administered into the RVM significantly reduced morphine analgesia on the tail-flick and jump tests elicited w x from the vlPAG 18,19 . Opioid receptors in the RVM also modulate mesencephalic morphine analgesia since either general, m or d antagonists significantly reduced this w x response 20 . Further, RVM microinjections of neu- rotensin or neurotensin antagonists respectively reduce or enhance morphine analgesia elicited from the vlPAG w x 58,59 . These effects were quite selective since these antagonists failed to alter baseline nociceptive latencies or thresholds in the RVM, and medullary cannulae placed lateral, dorsal or ventral to the RVM failed to support antagonist effects upon mesencephalic morphine analgesia. 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 01382-7