Psychopharmacology(1996) 127:225-230 9 Springer-Verlag 1996 David C. Jewett 9 Henry I. Mosberg James H. Woods Discriminative stimulus effects of a centrally administered, delta-opioid peptide (D-Pen2m-PenS-enkephalin) in pigeons Received: 26 April 1995 /Final version: 9 December 1995 Abstract The present study assessed the discriminative stimulus effects of the delta-opioid agonist [D-Pen2-D - PenS]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injec- tions of I00 ~tg [13-Pen2-D-PenS]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of dis- criminative control was rapid (14-28 daily sessions). [D- Ser 2, Leu 5, Thrrlenkephalin (DSLET) and [D-AlaZ]del - torphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032-100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01-1 mg/kg, IM), and the mu-opioid agonists, DAMGO (0.1-3.2 p,g, ICV) and morphine (1-10 mg/kg, IM), did not produce dis- criminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrin- dole (0.1 mg/kg, IM), an antagonist selective for delta- opioid receptors, produced approximately a 30-fold re- duction in the potency of DPDPE. DPDPE's discrimina- tive stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo. Key words [t)-Pen2-D-PenS]enkephalin (DPDPE) 9 [D-Ser 2, Leu 5, Thr6]enkephalin (DSLET) 9 [t)-Ala2]deltorphin II 9 BW373U86 9 Drug discrimination 9 Pigeons 9 Delta opioids 9 Operant behavior D. C. Jewett (F~) - J. H. Woods Department of Pharmacology. University of Michigan Medical School, 1301 MSRB III. Ann Arbor, MI 48109-0632, USA H. I. Mosberg Department of Medicinal Chemistry. University of Michigan Medical School, Ann Arbor. MI 48109-0632. USA Introduction Opioids produce their effects through three major types of opioid receptors, mu, kappa, and delta. Drug discrimina- tion studies using receptor-selective agonists and antago- nists have made important contributions in characterizing these receptors. Distinct discriminative stimulus effects of mu- and some kappa-opioid agonists have been character- ized in pigeons. For example, bremazocine produced dis- criminative stimulus effects similar to those of another highly selective kappa agonist, U50,488, but neither pro- duced morphine-like discriminative stimulus effects (Pick- er and Dykstra 1987; although some kappa-opioid ago- nists do produce morphine-like discriminative effects, see Herling et al. 1980). A larger dose of naloxone is required to reduce the potency of U50,488 as a discriminative stim- ulus than is required to reduce morphine's potency (Picker and Dykstra 1987). Discriminative stimulus effects of del- ta-opioid receptor agonists, however, have not been stud- ied extensively. One possible reason for the paucity of drug discrimination information on delta-opioid agonists is that most agonists at delta-opioid receptors are peptides, have difficulty crossing the blood-brain barrier, and proba- bly need to be administered centrally. To date, only one study has demonstrated discrimina- tive stimulus effects mediated through a delta-opioid re- ceptor (Comer et al. 1993). The discriminative stimulus effects of IM BW373U86 were antagonized by small doses of naltrindole, which is more potent in antagoniz- ing delta-opioid effects than mu- or kappa-opioid medi- ated effects. Interestingly, central administration of the prototypic delta-opioid receptor agonists DPDPE and DSLET did not produce a discriminative stimulus similar to that of BW373U86. Additionally, a portion of BW373U86's discriminative stimulus effects were shared with mu-opioid agonists. Systemically adminis- tered morphine, alfentanil, and etonitazene all produced partial generalization to the BW373U86 discriminative stimulus, and BW373U86 partially generalized to mor- phine in pigeons trained to discriminate 5.6 mg/kg mor- phine from saline.