Ž . European Journal of Pharmacology 387 2000 R1–R3 www.elsevier.nlrlocaterejphar Rapid communication Cyclo-oxygenase-inhibitors increase morphine effects on mesolimbic dopamine neurons Miriam Melis a , Marco Diana b , Gian Luigi Gessa a, ) a Department of Neuroscience, ‘‘B.B. Brodie’’, UniÕersity of Cagliari, Õia Porcell, 4, 09124 Cagliari, Italy b Department of Drug Sciences, UniÕersity of Sassari, Õia Muroni 23 r a, 07100, Sassari, Italy Received 11 November 1999; accepted 16 November 1999 Abstract The effect of cyclo-oxygenase inhibitors, indomethacin and nimesulide, on the action of i.v. morphine on dopamine neurons projecting to the nucleus Accumbens was studied using standard extracellular recording techniques coupled with antidromic identification in Ž . Ž . unanesthetized rats. The i.v. administration of either nimesulide 3 mgrkg or indomethacin 3.5 mgrkg per se did not affect the firing Ž . rate of mesolimbic dopamine cells. In contrast, the subsequent administration of morphine 0.25–2 mgrkg i.v. potently increased the firing rate of mesolimbic dopamine neurons in cyclo-oxygenase inhibitor-pretreated rats as compared with saline-pretreated rats. The maximal enhancement of basal firing rate at the highest dose of morphine tested was 92%, 80% and 47%, for nimesulide-, indomethacin-, and saline-treated rats, respectively. Our results indicate that the effect of morphine on mesolimbic dopamine cells is potentiated by blocking cyclo-oxygenase activity and suggest that the modulation of cyclo-oxygenase pathway in dopamine cells might be involved in the cellular mechanisms of the rewarding actions of morphine. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Dopamine; Electrophysiology; Morphine It has been proposed recently that cyclo-oxygenase inhibitors, such as indomethacin and acetylsalicylic acid, potentiate the suppressing effect of opioids on presynaptic Ž . g-amino butyric acid GABA neurotransmission in peri- aqueductal Grey neurons, which is involved in the anal- Ž . gesic effects of opioids Vaughan, 1998 . Similarly, mor- phine in vitro hyperpolarizes GABA interneurons in the Ž pars reticulata of the substantia nigra Johnson and North, . 1992 and reduces their spontaneous electrical activity in Ž . vivo Finnerty and Chan, 1979 . Such decreased synaptic Ž input to dopamine cells leads to their disinhibition Mat- . thews and German, 1984 , a m-opioid receptor mediated effect, which appears to be important for the euphorigenic Ž . properties of morphine Wise, 1987 . Since the periaque- ductal grey also plays a role in the reinforcing properties Ž . of systemic morphine Cazala, 1990 , and this effect is blocked by naloxone, it is tempting to speculate that the neural substrates of both the reinforcing and analgesic properties of morphine are at least partially overlapping ) Corresponding author. Tel.: q0039-70-6758417; fax: q0039-70- 657237. Ž . E-mail address: lgessa@unica.it G.L. Gessa Ž . Franklin, 1998 . In order to verify this hypothesis, we studied the effect of intravenous morphine on the firing rate and pattern of antidromically identified mesolimbic dopamine neurons after pre-treatment with two cyclo- oxygenase inhibitors, either nimesulide or indomethacin, using standard extracellular recordings coupled with an- tidromic identification in unanesthetized rats. Experiments were carried out in non-anesthetized rats because general anesthetics modify both the firing rate and pattern of dopamine neurons and their response to phar- Ž macological agents, including morphine Matthews and . Ž German, 1984 . Male Sprague–Dawley albino rats 200– . 225 g were used in all experiments. All subjects were kept on a 12 hr12 h lightrdark cycle with food and water available ad libitum. Experimental protocols were ap- Ž . proved by the Ethical Committee EC of the University of Cagliari and performed in strict accordance with EC regu- Ž lations for the care and use of experimental animals CEE . N886r609 . Electrophysiological experiments were per- Ž . formed as already described Diana et al., 1998 . Dopamine neurons were identified according to well established elec- trophysiological characteristics including antidromic acti- vation from the nucleus accumbens and collision of an antidromically elicited spike with spontaneously occurring 0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 99 00799-2