Glycine inhibitory dysfunction induces a selectively dynamic, morphine-resistant, and neurokinin 1 receptor- independent mechanical allodynia.
Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. We recently provided a novel perspective on the mechanisms of this symptom by showing that a simple switch in trigeminal glycine synaptic inhibition can turn touch into pain by unmasking innocuous input to superficial dorsal horn nociceptive specific neurons through a local excitatory, NMDA-dependent neural circuit involving neurons expressing the gamma isoform of protein kinase C. Here, we further investigated the clinical relevance and processing of glycine disinhibition. First, we showed that glycine disinhibition with strychnine selectively induced dynamic but not static mechanical allodynia. The induced allodynia was resistant to morphine. Second, morphine did not prevent the activation of the neural circuit underlying allodynia as shown by study of Fos expression and extracellular-signal regulated kinase phosphorylation in dorsal horn neurons. Third, in contrast to intradermal capsaicin injections, light, dynamic mechanical stimuli applied under disinhibition did not produce neurokinin 1 (NK1) receptor internalization in dorsal horn neurons. Finally, light, dynamic mechanical stimuli applied under disinhibition induced Fos expression only in neurons that did not express NK1 receptor. To summarize, the selectivity and morphine resistance of the glycine-disinhibition paradigm adequately reflect the clinical characteristics of dynamic mechanical allodynia. The present findings thus reveal the involvement of a selective dorsal horn circuit in dynamic mechanical allodynia, which operates through superficial lamina nociceptive-specific neurons that do not bear NK1 receptor and provide an explanation for the differences in the pharmacological sensitivity of neuropathic pain symptoms.
Miraucourt
Loïs S
LS
INSERM, U929, F-63000 Clermont-Ferrand, France.
Moisset
Xavier
X
Dallel
Radhouane
R
Voisin
Daniel L
DL
D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D004351:Drug Resistance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D017711:Nonlinear Dynamics; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation / Q000379:methods; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D013331:Strychnine
D000701:Analgesics, Opioid; D018756:GABA Antagonists; D016761:Oncogene Proteins v-fos; D018040:Receptors, Neurokinin-1; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases; D013331:Strychnine; D002211:Capsaicin; D005998:Glycine; D001640:Bicuculline