Vol. 295, Issue 3, 1142-1148, December 2000

Inhibition of Morphine Tolerance Development by a Substance P-Opioid Peptide Chimera¹

Stacy E. Foran, Daniel B. Carr, Andrzej W. Lipkowski, Iwona Maszczynska , James E. Marchand, Aleksandra Misicka, Martin Beinborn, Alan S. Kopin² and Richard M. Kream

Departments of Anesthesiology and Pharmacology and Experimental Therapeutics, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts (S.E.F., D.B.C., I.M., J.E.M., R.M.K.); Neuropeptide Laboratory Medical Research Center, Polish Academy of Sciences, Warsaw, Poland (A.W.L., I.M., A.M.); and Department of Medicine and Center for Gastroenterology Research on Absorptive and Secretory Processes (GRASP) Digestive Center, New England Medicine Center, Tufts University School of Medicine, Boston, Massachusetts (M.B., A.S.K.)

The neuropeptide substance P (SP), apart from its traditional role in spinal nociceptive processing, is an important regulatory effector of opioid-dependent analgesic processes. The present study stems from our original findings indicating that 1) pharmacologically administered SP mediates a strong inhibitory activity on the development of morphine tolerance in rats, and that 2) a novel SP-opioid peptide chimera YPFFGLM-NH₂, designated ESP7, produces opioid-dependent analgesia without tolerance development. To further examine the effects of simultaneous activation of two distinct opposing spinal systems on opioid tolerance and the mechanisms underlying chimeric peptide function, a second SP-opioid chimera was synthesized. This chimera, designated ESP6 (YPFFPLM-NH₂), contains overlapping domains of endomorphin-2 and SP, respectively. ESP6 is distinguished from ESP7 by a glycine to proline substitution at position 5. Intrathecal administration of morphine sulfate (MS) with ESP6 leads to a prolongation of MS analgesia over a 5-day period. The analgesia produced by ESP6 and MS is opioid receptor-dependent, due to the ability of naltrexone to block the analgesic response. Furthermore, when ESP6 and MS are administered with concurrent NK-1 receptor blockade, a decay in analgesic potency similar to that seen with MS alone results. The presence of a proline in ESP6 appears to reduce its conformational flexibility, limit its potency at the µ-opioid receptor, and hinder its analgesic effectiveness alone. However, ESP6 represents a novel adjuvant for the maintenance of opioid analgesia over time and provides a means to predict the pharmacological properties of a chimera from its structure.