Light touch induces ERK activation in superficial dorsal horn neurons after inflammation: involvement of spinal astrocytes and JNK signaling in touch-evoked central sensitization and mechanical allodynia.
Activation of extracellular signal-regulated kinase (ERK) in spinal cord neurons could serve as a marker for sensitization of dorsal horn neurons in persistent pain. ERK is normally activated by high-threshold noxious stimuli. We investigated how low-threshold mechanical stimuli could activate ERK after complete Freund's adjuvant (CFA)-induced inflammation. Unilateral injection of CFA induced ipsilateral heat hyperalgesia and bilateral mechanical allodynia. CFA-induced ERK activation in ipsilateral dorsal horn neurons declined after 2 days. Interestingly, low-threshold mechanical stimulation given by light touch either on the inflamed paw or the contralateral non-inflamed paw dramatically increased ERK phosphorylation in the dorsal horn ipsilateral to touch stimulation. Notably, light touch induced ERK phosphorylation mainly in superficial neurons in laminae I-IIo. Intrathecal administration of the astroglial toxin L-α-aminoadipate on post-CFA day 2 reversed CFA-induced bilateral mechanical allodynia but not heat hyperalgesia. Furthermore, L-α-aminoadipate, the glial inhibitor fluorocitrate, and a peptide inhibitor of c-Jun N-terminal Kinase all reduced light touch-evoked ERK activation ipsilateral to touch. Collectively, these data suggest that (i) ERK can be activated in superficial dorsal horn neurons by low-threshold mechanical stimulation under pathological condition and (ii) ERK activation by light touch is associated with mechanical allodynia and requires an astrocyte network.
Gao
Yong-Jing
YJ
Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. yjing@zeus.bwh.harvard.edu
Ji
Ru-Rong
RR
D015074:2-Aminoadipic Acid / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D002951:Citrates / Q000494:pharmacology; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005620:Freund's Adjuvant; D007839:Functional Laterality; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010812:Physical Stimulation / Q000379:methods; D020671:Posterior Horn Cells / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology*; D014110:Touch
D002951:Citrates; D018691:Excitatory Amino Acid Antagonists; D010455:Peptides; D015074:2-Aminoadipic Acid; C007744:fluorocitrate; D005620:Freund's Adjuvant; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C478085:D-JNKI-1