title: Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat.
abstract: Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.
authors.affiliation: Division of Neuroscience, Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Joseph
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002772:Cholera Toxin / Q000378:metabolism; D003545:Cysteine / Q000009:adverse effects / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004357:Drug Synergism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology / Q000627:therapeutic use; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000009:adverse effects; D006735:Horseradish Peroxidase / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009619:Nociceptors / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000009:adverse effects; D014665:Vasodilator Agents / Q000009:adverse effects
chemical_list: D000701:Analgesics, Opioid; D051100:Glial Cell Line-Derived Neurotrophic Factor; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D026403:S-Nitrosothiols; D014665:Vasodilator Agents; C052635:cholera toxin, B subunit-horseradish peroxidase; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002772:Cholera Toxin; C021315:S-nitrosocysteine; D006735:Horseradish Peroxidase; D003545:Cysteine