Pharmacology Biochemistry &Behavior, Vol. 41. pp. 654i7. ©Pergamon Press plc, 1991. Printed in the U.S.A. 0091-3057/92 $5.00 + .00 Evidence of Hyperglycemic Hyperalgesia by Quinpirole DAVID S. ROANE* AND DENNIS PAULt *Division of Pharmacology and Toxicology, School of Pharmacy, Northeast Louisiana University, Monroe, LA 71270 i'Department of Pharmacology, Louisiana State University Medical Center 1900 Perdido Street, New Orleans, LA 70112 Received 3 September 1991 ROANE, D. S. AND D. PAUL. Evidence of hyperglycemic hyperalgesia by quinpirole. PHARMACOL BIOCHEM BEHAV 41(1) 65-67, 1992.--Male albino rats were tested for antinociception following injections (IP) with saline, quinpirole (Quin) (1 mg/kg), morphine sulfate (M.S.) (5 mg/kg), or both Quin and M.S. (1 mg/kg and 5 mg/kg, respectively). Quin reduced and M.S. increased tail-flick latency as compared to controls. Tail-flick latencies of the animals injected with both drugs were significantly reduced as compared M.S. alone. Quin increased blood glucose levels by 96 percent, as compared to saline controls. In competi- tive binding studies Quin displaced 3H-DAGO (IC5o= 29.8 p.M). CD-1 mice demonstrated a naloxone-reversible analgesia follow- ing ICV Quin (100 i~g). These data are consistent with the hypothesis that the hyperglycemic effects of Quin attenuate M.S. analgesia while the antinociceptive effects of Quin may be mediated through opioid receptors. Antinociception Analgesia Hyperglycemia Quinpirole D-2 agonist Glucose Opioid receptor THE elevation of plasma glucose, produced either by streptozo- tocin pretreatment (6, 9, 10) or by simple IP injection of sugars (4) attenuates the antinociceptive potency of morphine (M.S.). The mechanism of action of this phenomenon is unknown, though there appears to be some involvement of CNS cellular energetics, including ATP synthesis (10) and an ATP-sensitive K ÷ channel (5). It has been reported that the dopamine-2 recep- tor agonist, quinpirole (Quin) elevates plasma and brain glucose via a central D-2 mechanism when the drug is administered in small doses, peripherally (8). This raises the possibility that Quin might interfere with M.S.-mediated antinociception via a hyperglycemic effect, in spite of the fact that Quin, at higher doses, possesses analgesic properties (7). METHOD Male Sprague-Dawley rats, 250-350 g, were housed under standard conditions in individual cages on a 12-h light cycle (lights on at 0700 h) with ad lib access to Purina Rat chow and water. All procedures were begun at 0800 and completed by 1100 h. Nociceptive thresholds were assessed by the tail-flick method of D'Amour and Smith (1) with the stimulus intensity set to elicit a response from control animals at 5.5---0.5 s. All animals were handled daily for three days and were subjected to the tail- flick procedure on two consecutive days prior to drug testing. Morphine sulfate (M.S.) (NIDA Drug Supply System, Rock- ville) and quinpirole HC1 (Quin) (RBI, Natick, MA) were placed in solution at concentrations of 5 and 1 mg/ml, respectively. Drugs were administered 1 ml/kg body weight, IP, 30 minutes prior to tail-flick testing. Control animals received saline in equivalent volumes. Blood samples for glucose analysis were taken from the tails of the animals immediately following the nociceptive tests. Plasma glucose was assayed by glucose oxidase method adapted for a YSI Model 23A Glucose Analyzer (Yellow Springs, OH). Rat brain membranes for mu opioid receptor binding were prepared by homogenizing tissue in 50 volumes of 0.32 M su- crose-50 mM Hepes buffer, pH 7.4 in a glass vessel with a tef- lon pestle. The resulting suspension was centrifuged at 1000 × g for 8 min. The supernatant was decanted, centrifuged and washed three times at 30,000 x g in 50 mM Hepes HC1, pH 7.4. The resulting pellet was resuspended in 50 volumes of Hepes buffer. For binding analysis, 500 ixl of membranes were used to make up 1 ml final volumes containing 4.8 nM 3H-DAGO ([D- Ala 2, N-Me-Phe 4, Gly-ol 5] enkephalin) (NEN, Boston, MA) with Quin concentrations ranging from 1 x 10- ~ M to 1.22 x 10 -o4 M. Nonspecific binding was determined by 3H-DAGO binding in the presence of l0 I~M cold DAGO and total binding was determined by the binding of 4.8 nM 3H-DAGO in the presence of no competitors. Incubations were carried out at 25°C for 90 min. Samples were poured over Whatman GFB filters on a vacuum manifold and washed with 3 x 5 ml of ice-cold buffer. Filters were dried and counted by standard scintillation tech- niques. Displacement curves and estimation of the IC5o of Quin for the mu receptor were obtained by use of the ALLFIT pro- gram with the "a" and "d" parameters restricted to values of 100 and 0, respectively (2). The mouse Quin-analgesia studies used CD-1 mice main- tained under standard conditions. The D'Amour and Smith tail- flick method was used to establish baseline latencies with the mean of two trails in the range of 3--4 s. Posttreatment tail-flick latencies were determined 20 min after central injections. Mice doubling their baseline latency were considered analgesic. A maximal latency of 12 s was used to minimize tissue damage. 65