title: Distinct terminal and cell body mechanisms in the nociceptor mediate hyperalgesic priming.
abstract: Hyperalgesic priming, a form of neuroplasticity in nociceptors, is a model of the transition from acute to chronic pain in the rat, which involves signaling from the site of an acute tissue insult in the vicinity of the peripheral terminal of a nociceptor to its cell body that, in turn, induces a signal that travels back to the terminal to mediate a marked prolongation of prostaglandin E2-induced hyperalgesia. In the present experiments, we studied the underlying mechanisms in the cell body and compared them to the mechanisms in the nerve terminal. Injection of a cell-permeant cAMP analog, 8-bromo cAMP, into the dorsal root ganglion induced mechanical hyperalgesia and priming with an onset more rapid than when induced at the peripheral terminal. Priming induced by intraganglion 8-bromo cAMP was prevented by an oligodeoxynucleotide antisense to mRNA for a transcription factor, cAMP response element-binding protein (CREB), and by an inhibitor of importin, which is required for activated CREB to get into the nucleus. While peripheral administration of 8-bromo cAMP also produced hyperalgesia, it did not produce priming. Conversely, interventions administered in the vicinity of the peripheral terminal of the nociceptor that induces priming-PKCε activator, NGF, and TNF-α-when injected into the ganglion produce hyperalgesia but not priming. The protein translation inhibitor cordycepin, injected at the peripheral terminal but not into the ganglion, reverses priming induced at either the ganglion or peripheral terminal of the nociceptor. These data implicate different mechanisms in the soma and terminal in the transition to chronic pain.
authors: Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143.
authors: Luiz F
authors: LF
authors: Ferrari
authors: Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143.
authors: Dioneia
authors: D
authors: Araldi
authors: Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143 jon.levine@ucsf.edu.
authors: Jon D
authors: http://orcid.org/0000-0003-0681-5545
authors: JD
authors: Levine
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000633:toxicity; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D018932:Chemokine CCL2 / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D003609:Dactinomycin / Q000378:metabolism; D015232:Dinoprostone / Q000633:toxicity; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D006930:Hyperalgesia / Q000209:etiology* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D009619:Nociceptors / Q000166:cytology* / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation / Q000009:adverse effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D017362:Cyclic AMP Response Element-Binding Protein; D020319:Oligodeoxyribonucleotides, Antisense; D003609:Dactinomycin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D051744:Protein Kinase C-epsilon; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015232:Dinoprostone
keywords: dorsal root ganglion; hyperalgesic priming; mechanical hyperalgesia; nociceptor; rat