title: CGRP receptor blockade by MK-8825 alleviates allodynia in infraorbital nerve-ligated rats.
abstract: BACKGROUND
  Previous data showed that, in rats, anti-migraine drugs (triptans, olcegepant) significantly reduced mechanical allodynia induced by infraorbital nerve (ION) ligation but not that evoked by sciatic nerve (SN) ligation. Whether this also occurs with MK-8825, a novel anti-migraine drug also acting through CGRP receptor blockade (but chemically unrelated to olcegepant) was tested in the present study, which also investigated possible anti-neuroinflammatory effects of this drug.
  
  
  METHODS
  Adult male Sprague-Dawley rats underwent unilateral chronic constriction injury (CCI) to either the ION or the SN, and mechanical allodynia was assessed 2 weeks later within the ipsilateral vibrissae territory or hindpaw, respectively. Transcripts of neuroinflammatory markers were quantified by real-time quantitative RT-PCR in ipsilateral trigeminal ganglion and spinal trigeminal nucleus in CCI-ION rats.
  
  
  RESULTS
  Acute as well as repeated (for 4 days) administration of MK-8825 (30-100 mg/kg, i.p.) significantly reduced CCI-ION-induced mechanical allodynia but was ineffective in CCI-SN rats. CCI-ION was associated with marked up-regulation of neuronal and glial inflammatory markers (ATF3, IL6, iNOS, COX2) in ipsilateral trigeminal ganglion but not spinal trigeminal nucleus. MK-8825-induced inhibition of iNOS mRNA up-regulation probably underlay its anti-allodynic effect because pharmacological blockade of iNOS by AMT (6 mg/kg, s.c.) mimicked this effect.
  
  
  CONCLUSIONS
  These data further support the idea that CGRP receptor blockade might be a valuable approach to alleviate trigeminal, but not spinal, neuropathic pain through, at least partly, an inhibitory effect on neuropathic pain-associated increase in NO production in trigeminal ganglion.
authors.affiliation: INSERM U894, CPN, Paris, France; Neuropsychopharmacology, Faculty of Medicine Pierre & Marie Curie, University Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Michot
authors.forename: V
authors.initials: V
authors.lastname: Kayser
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: S
authors.initials: S
authors.lastname: Bourgoin
mesh_terms: D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006930:Hyperalgesia / Q000209:etiology*; D008026:Ligation / Q000379:methods; D008297:Male; D009437:Neuralgia / Q000139:chemically induced; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries*; D020426:Sciatic Neuropathy / Q000188:drug therapy*; D013141:Spiro Compounds / Q000494:pharmacology*; D012668:Trigeminal Ganglion / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; C575097:MK-8825; D011725:Pyridines; D018015:Receptors, Calcitonin Gene-Related Peptide; D013141:Spiro Compounds