The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor.
The p75 neurotrophin receptor (p75NTR) and its activation of the sphingomyelin signaling cascade are essential for mechanical hypersensitivity resulting from locally injected nerve growth factor (NGF). Here the roles of the same effectors, and of the tropomyosin receptor kinase A (TrkA) receptor, are evaluated for thermal hyperalgesia from NGF. Sensitivity of rat hind paw plantar skin to thermal stimulation after local sub-cutaneous injection of NGF (500ng) was measured by the latency for paw withdrawal (PWL) from a radiant heat source. PWL was reduced from baseline values at 0.5-22h by ∼40% from that in naïve or vehicle-injected rats, and recovered to pre-injection levels by 48h. Local pre-injection with a p75NTRblocking antibody did not affect the acute thermal hyperalgesia (0.5-3.5h) but hastened its recovery so that it had reversed to baseline by 22h. In addition, GW4869 (2mM), an inhibitor of the neutral sphingomyelinase (nSMase) that is an enzyme in the p75NTRpathway, also failed to prevent thermal hyperalgesia. However, C2-ceramide, an analog of the ceramide produced by sphingomyelinase, did cause thermal hyperalgesia. Injection of an anti-TrkA antibody known to promote dimerization and activation of that receptor, independent of NGF, also caused thermal hyperalgesia, and prevented the further reduction of PWL from subsequently injected NGF. A non-specific inhibitor of tropomyosin receptor kinases, K252a, prevented thermal hyperalgesia from NGF, but not that from the anti-TrkA antibody. These findings suggest that the TrkA receptor has a predominant role in thermal hypersensitivity induced by NGF, while p75NTRand its pathway intermediates serve a modulatory role.
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
Alla
A
Khodorova
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Grant D
GD
Nicol
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: gstrichartz@partners.org.
Gary
G
Strichartz
D000700:Analgesics / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D001597:Benzylidene Compounds / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D014110:Touch
D000700:Analgesics; D000814:Aniline Compounds; D000906:Antibodies; D001597:Benzylidene Compounds; D002227:Carbazoles; D004791:Enzyme Inhibitors; C468773:GW 4869; D026121:Indole Alkaloids; C064769:N-acetylsphingosine; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C068313:Ngfr protein, rat; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D020917:Receptor, trkA; D011493:Protein Kinase C; D013110:Sphingosine
TRPV1; atypical PKC; hypersensitivity; neurotrophin; pain