Medullary pain facilitating neurons mediate allodynia in headache‐related pain

Abstract

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 hindpaws were characterized.RESULTS-IM elicited robust facial and hindpaw allodynia which peaked within 3 hr. 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 treatment of migraine, including sumatriptan, naproxen, and a CGRP-antagonist. Consistent with clinical observations the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw 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 following IM.INTERPRETATION-Facial and hindpaw 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.

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

“…These data echo the finding of CGRP antagonists and/or sumatriptan attenuated facial allodynia triggered by inflammation or NO in models of headache. 28,82 Trigeminal allodynia was not different in iNOS knockout and WT injured groups at 2 weeks, which may be explained by CGRP levels being well above control levels. In contrast, nNOS and iNOS inhibitors attenuated mechanical hypersensitivity after nerve injury.…”

“…44 Inflammation, hyperactivation, or circuit disruptions within the brain's central nociceptive pathways cannot be ruled out as a generator of PTH. 7,48,78,[80][81][82] Interactions between CGRP-and iNOS/NO-signaling pathways may converge in the thalamus eliciting photosensitivity. Neurons in the posterior thalamus respond dually to input from dural nociceptors (trigeminal ganglion cells) and photoreceptors (retinal ganglion cells) 24,83 ; this pathway is proposed to explain photosensitivity during primary and, perhaps, PTH.…”

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

“…The holding temperature obviates any concern that apparent effects on reflex latency could be attributed to changes in skin temperature. Previous work has shown that response latencies and neuronal response properties are stable for a period of several hours with this testing protocol (Edelmayer et al 2009;Heinricher et al 2004Heinricher et al , 2010Kincaid et al 2006;Martenson et al 2009). …”

Migraine: A Multi-Modulation Process

“…However, it becomes evident recently that the descending control from the brainstem is bidirectional and there is a dynamic balance between the pain inhibition and facilitation [13], which can be altered in pathological states. Brainstem alterations have been widely discovered in migraineurs [9,14,15], supporting its' modulatory function in the disease.…”

“…The TCC and thalamus also receive projections from several nociceptive modulatory brain regions, and sensitization of neurons in the two regions has great impacts in the process of headache chronification. Also, the sensitization of TCC and thalamus is believed to be the underlying mechanisms of allodynia [8,9], a common physical sign in migraine patients, featured by increased skin sensitivity in the referred pain area and even the other side of the head or the forearm.…”