Medullary pain facilitating neurons mediate allodynia in headache-related pain

• Published in: Annals of neurology Vol. 65; no. 2; pp. 184 - 193
• Main Authors: Edelmayer, Rebecca M., Vanderah, Todd W., Majuta, Lisa, Zhang, En-Tan, Fioravanti, Beatriz, De Felice, Milena, Chichorro, Juliana G., Ossipov, Michael H., King, Tamara, Lai, Josephine, Kori, Shashi H., Nelsen, Andrew C., Cannon, Keri E., Heinricher, Mary M., Porreca, Frank
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2009; Wiley-Liss
• Subjects: Action Potentials - physiology; Animals; Anti-Inflammatory Agents - therapeutic use; Biological and medical sciences; Bradykinin - administration & dosage; Dinoprostone - administration & dosage; Disease Models, Animal; Dose-Response Relationship, Drug; Dura Mater - pathology; Dura Mater - physiology; Fundamental and applied biological sciences. Psychology; Headache Disorders - complications; Headache Disorders - drug therapy; Headache Disorders - pathology; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - pathology; Male; Medical sciences; Medulla Oblongata - pathology; Medulla Oblongata - physiopathology; Neurology; Neurons - drug effects; Neurons - physiology; Neurotransmitter Agents - pharmacology; Oncogene Proteins v-fos - metabolism; Pain Measurement - methods; Pain Threshold - drug effects; Pain Threshold - physiology; Rats; Rats, Sprague-Dawley; Serotonin - administration & dosage; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Tripelennamine - administration & dosage; Vertebrates: nervous system and sense organs; Allodynia; Headache; Nervous system diseases; Pain; Neuron; Neurological disorder
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21537

Objective To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. Methods Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind‐paws were characterized. Results IM elicited robust facial and hind‐paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene–related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin‐1 antagonist. Having established facial and hind‐paw allodynia as a useful animal surrogate of headache‐associated allodynia, we next showed that blocking pain‐facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain‐facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM‐induced allodynia. Electrophysiological studies confirmed activation of pain‐facilitating RVM “on” cells and transient suppression of RVM “off” cells after IM. Interpretation Facial and hind‐paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders. Ann Neurol 2009;65:184–193