Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral delta-opioid receptors.
The possible antihyperalgesic and antiallodynic activity of loperamide, an opioid agonist which does not readily penetrate the blood-brain barrier, were examined in the spinal nerve ligation model of experimental neuropathic pain. Intraperitoneal (i.p.) injection of loperamide effectively reversed thermal hyperalgesia. In contrast, loperamide had minimal effects on cold allodynia and no effects on mechanical allodynia. The antihyperalgesic action of loperamide against noxious heat was antagonized by naltrindole, a delta-opioid receptor selective antagonist, but not by pretreatment with beta-funaltrexamine, a mu-opioid receptor selective antagonist, or administration of nor-binaltorphimine, a kappa-opioid receptor selective antagonist. Furthermore, i.p. injection of [d-Ala(2), Glu(4)]-deltorphin II, a delta-opioid receptor selective peptide agonist, also reversed thermal hyperalgesia. The present results suggest that thermal hyperalgesia in experimental neuropathic pain can be reduced through activation of peripheral delta-opioid receptors. The data suggest the possible application of peripherally restricted and delta-opioid receptor selective agonists in the treatment of some aspects of neuropathic pain without many of the side effects associated with centrally acting opioids and without the peripheral side effects of opioid agonists acting at mu-receptors.
Shinoda
Katsumi
K
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411-8731, Japan.
Hruby
Victor J
VJ
Porreca
Frank
F
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D006930:Hyperalgesia / Q000188:drug therapy; D008139:Loperamide / Q000627:therapeutic use*; D008297:Male; D009292:Narcotic Antagonists / Q000008:administration & dosage; D009294:Narcotics / Q000008:administration & dosage; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000502:physiology*
D000700:Analgesics; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D008139:Loperamide