Hypothesis on reciprocal interactions between the central and peripheral components of the endogenous opioid system.
A hypothesis on reciprocal interactions between the central and peripheral components of the endogenous opioid system was formulated on the basis of results of our experimental studies and published data. In order to verify this hypothesis, we studied the effects of peripheral administration of loperamide (mu-opioid receptor agonist) and methylnaloxone (opioid receptor antagonist) not penetrating through the blood-brain barrier on the pain sensitivity of rats, morphine-induced analgesia, and formation of morphine analgesia tolerance. Peripheral loperamide and methylnaloxone modulated the central mechanisms of perception of painful stimuli. This fact confirmed the hypothesis on the reciprocal interactions between the central and peripheral compartments of the endogenous opioid system. Methylnaloxone exhibits an antagonistic effect on peripheral mu-opioid receptors, which probably leads to activation of the central mu-opioid receptors and to the development of analgesia. Loperamide activates peripheral, but suppresses the central mu-opioid receptors, which leads to hyperalgesia. Methylnaloxone suppresses morphine-induced analgesia under conditions of morphine activation of the central antinociceptive mechanisms. Peripheral injection of mu-opioid agonist loperamide virtually did not modify the central compartments of the opioid system under conditions of morphine treatment. Methylnaloxone and loperamide partially prevented the development of morphine analgesia tolerance. Hence, the results confirm the hypothesis about the reciprocal interactions between the central and peripheral compartments of the endogenous opioid system. The relationships between the central and peripheral compartments of the opioid system can be more intricate when its function is modulated.
Sudakov
S K
SK
P. K. Anokhin Institute of Physiology, the Russian Academy of Medical Sciences, Moscow, Russia. s-sudakov@mail.ru
Trigub
M M
MM
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004361:Drug Tolerance / Q000502:physiology; D008139:Loperamide / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010111:Oxymorphone / Q000008:administration & dosage / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D008139:Loperamide; D009020:Morphine; D010111:Oxymorphone