Protein Kinase C γ Interneurons Mediate C-fiber–induced Orofacial Secondary Static Mechanical Allodynia, but Not C-fiber–induced Nociceptive Behavior

• Published in: Anesthesiology (Philadelphia) 2016-05, Vol.124 (5), p.1136-1152
• Main Authors: Peirs, Cedric, Bourgois, Nathalie, Artola, Alain, Dallel, Radhouane
• Format: Article
• Language: English
• Subjects: Animals; Bicuculline - pharmacology; Capsaicin; Excitatory Amino Acid Antagonists - pharmacology; Hyperalgesia - chemically induced; Hyperalgesia - physiopathology; Hyperalgesia - psychology; Interneurons; Life Sciences; Male; Mechanoreceptors - drug effects; Nerve Fibers, Unmyelinated; Pain - chemically induced; Pain - physiopathology; Pain - psychology; Phosphorylation; Posterior Horn Cells; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Receptors, GABA-B - drug effects
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000001000

BACKGROUND:Tissue injury enhances pain sensitivity both at the site of tissue damage and in surrounding uninjured skin (secondary hyperalgesia). Secondary hyperalgesia encompasses several pain symptoms including pain to innocuous punctate stimuli or static mechanical allodynia. How injury-induced barrage from C-fiber nociceptors produces secondary static mechanical allodynia has not been elucidated. METHODS:Combining behavioral, immunohistochemical, and Western blot analysis, the authors investigated the cell and molecular mechanisms underlying the secondary static mechanical allodynia in the rat medullary dorsal horn (MDH) using the capsaicin model (n = 4 to 5 per group). RESULTS:Intradermal injection of capsaicin (25 μg) into the vibrissa pad produces a spontaneous pain and a secondary static mechanical allodynia. This allodynia is associated with the activation of a neuronal network encompassing lamina I–outer lamina III, including interneurons expressing the γ isoform of protein kinase C (PKCγ) within inner lamina II (IIi) of MDH. PKCγ is concomitantly phosphorylated (+351.4 ± 79.2%, mean ± SD; P = 0.0003). Mechanical allodynia and innocuous punctate stimulus–evoked laminae I to III neuronal activation can be replicated after intracisternally applied γ-aminobutyric acid receptor type A (GABAA) antagonist (bicuculline0.05 μg) or reactive oxygen species (ROS) donor (tert-butyl hydroperoxide50 to 250 ng). Conversely, intracisternal PKCγ antagonist, GABAA receptor agonist, or ROS scavenger prevent capsaicin-induced static mechanical allodynia and neuronal activation. CONCLUSIONS:Sensitization of lamina IIi PKCγ interneurons is required for the manifestation of secondary static mechanical allodynia but not for spontaneous pain. Such sensitization is driven by ROS and GABAAergic disinhibition. ROS released during intense C-fiber nociceptor activation might produce a GABAAergic disinhibition of PKCγ interneurons. Innocuous punctate inputs carried by Aδ low-threshold mechanoreceptors onto PKCγ interneurons can then gain access to the pain transmission circuitry of superficial MDH, producing pain.