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Effects of Pain and Analgesia on Intracranial Self-Stimulation (ICSS) in Rats

Gail Pereira Do Carmo, PhD, ADARC, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, William Carlezon, PhD, MRC, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, and S. Stevens Negus, PhD, Alcohol & Drug Abuse Res. Center, McLean Hospital--Harvard Medical School, 115 Mill St., Belmont, MA 02478.

The effective management of pain continues to be major clinical problem. Current preclinical models of pain focus on the measurement of pain-evoked behavior, which may yield false positives. Our laboratory has focused on methods development for assays of pain-suppressed behavior, which may complement existing assays. The present study compared the effects of IP lactic acid injections and morphine pretreatments on the writhing response (a pain-evoked behavior) and intracranial self-stimulation (ICSS; a behavior that may be suppressed by pain). For the ICSS procedure, Sprague Dawley rats implanted with electrodes in the lateral hypothalamus were tested on a FR1 schedule of reinforcement to respond for electrical stimulation. Response rates were measured across a descending series of 15 current frequencies, and rate-frequency curves were determined. Acid-induced writhing was measured over 60 min in a separate group of animals. Both writhing and ICSS were evaluated under baseline conditions and after treatment with lactic acid (0.32-3.2 %, IP) and/or morphine (1.0-10 mg/kg, IP). Lactic acid produced time- and concentration-dependent increases in writhing, with peak writhes occurring at 20 min. and subsiding by 60 min. Lactic acid also produced rightward shifts in the ICSS curve rate-frequency curves and increased ICSS thresholds. However, lactic acid was more potent in evoking writhing than in suppressing ICSS. Morphine dose-dependently reduced acid-evoked writhing, and effects of morphine on acid-suppressed ICSS are being evaluated now. ICSS may be an especially useful assay for evaluation of pain-suppressed behavior, because it is often used to assess reward threshold and "hedonic state" in rodents. Accordingly, ICSS may be useful for exploring interactions between pain and depression.