Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat.
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.
Joseph
E K
EK
Division of Neuroscience, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Levine
J D
JD
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
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