Inhibition of morphine tolerance development by a substance P-opioid peptide chimera

The neuropeptide substance P (SP), apart from its traditional role in spina l nociceptive processing, is an important regulatory effector of opioid-dep endent analgesic processes. The present study stems from our original findi ngs indicating that 1) pharmacologically administered SP mediates a strong inhibitory activity on the development of morphine tolerance in rats, and t hat 2) a novel SP-opioid peptide chimera YPFFGLM-NH2, designated ESP7, prod uces opioid-dependent analgesia without tolerance development. To further e xamine the effects of simultaneous activation of two distinct opposing spin al systems on opioid tolerance and the mechanisms underlying chimeric pepti de function, a second SP-opioid chimera was synthesized. This chimera, desi gnated ESP6 (YPFFPLM-NH2), contains overlapping domains of endomorphin-2 an d 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 t o the ability of naltrexone to block the analgesic response. Furthermore, w hen 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 flexibil ity, limit its potency at the mu -opioid receptor, and hinder its analgesic effectiveness alone. However, ESP6 represents a novel adjuvant for the mai ntenance of opioid analgesia over time and provides a means to predict the pharmacological properties of a chimera from its structure.