• Matthew F Lazenka, Kelen C Freitas, Sydney Henck, and S Stevens Negus.
• Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
• J. Pharmacol. Exp. Ther. 2017 Jul 1; 362 (1): 14-23.

AbstractClinically significant pain often includes a decrease in both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study compared effects of indirect and direct dopamine agonists in a preclinical assay of pain-depressed operant responding. Male Sprague-Dawley rats with chronic indwelling microelectrodes in the medial forebrain bundle were trained in an intracranial self-stimulation (ICSS) procedure to press a lever for pulses of electrical brain stimulation. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to depress ICSS. Intraperitoneal lactic acid-induced depression of ICSS was dose-dependently blocked by the dopamine transporter inhibitor methylphenidate and the D1-selective agonist SKF82958, but not by the D2/3-selective agonists quinpirole, pramipexole, or sumanirole. The antinociceptive effects of methylphenidate and SKF82958 were blocked by the D1-selective antagonist SCH39166. Acid-induced stimulation of a stretching response was evaluated in separate groups of rats, but all agonists decreased acid-stimulated stretching, and antagonism experiments were inconclusive due to direct effects of the antagonists when administered alone. Taken together, these results suggest that D1-receptor stimulation is both sufficient to block acid-induced depression of ICSS and necessary for methylphenidate antinociception in this procedure. Conversely, D2/3-receptor stimulation is not sufficient to relieve pain-depressed behavior. These results support the hypothesis that pain-related depression of dopamine D1 receptor signaling contributes to pain-related depression of behavior in rats. Additionally, these results support further consideration of indirect dopamine agonists and direct D1 receptor agonists as candidate treatments for pain-related behavioral depression.Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

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