Inhibition of morphine tolerance development by a substance P-opioid peptide chimera.
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-NH(2), 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-NH(2)), 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 micro-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.
Foran
S E
SE
Department of Anesthesiology and Pharmacology and Experimental Therapeutics, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Carr
D B
DB
Lipkowski
A W
AW
Maszczynska
I
I
Marchand
J E
JE
Misicka
A
A
Beinborn
M
M
Kopin
A S
AS
Kream
R M
RM
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013329:Structure-Activity Relationship; D013373:Substance P / Q000494:pharmacology*
D000701:Analgesics, Opioid; D007211:Indoles; D054833:Isoindoles; D009842:Oligopeptides; D018040:Receptors, Neurokinin-1; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; C105294:endomorphin 2; D009271:Naltrexone; D009020:Morphine