Chemical Stimulation of the Intracranial Dura Induces Enhanced Responses to Facial Stimulation in Brain Stem Trigeminal Neurons

Abstract

Chemical activation and sensitization of trigeminal primary afferent neurons innervating the intracranial meninges have been postulated as possible causes of certain headaches. This sensitization, however, cannot explain the extracranial hypersensitivity that often accompanies headache. The goal of this study was to test the hypothesis that chemical activation and sensitization of meningeal sensory neurons can lead to activation and sensitization of central trigeminal neurons that receive convergent input from the dura and skin. This hypothesis was investigated by recording changes in the responsiveness of 23 [16 wide-dynamic range (WDR), 5 high threshold (HT), and 2 low threshold (LT)] dura-sensitive neurons in nucleus caudalis to mechanical stimulation of their dural receptive fields and to mechanical and thermal stimulation of their cutaneous receptive fields after local application of inflammatory mediators or acidic agents to the dura. Responses to brief chemical stimulation were recorded in 70% of the neurons; most were short, lasting the duration of the stimulus only. Twenty minutes after chemical stimulation of the dura, the following changes occurred: 1) 95% of the neurons showed significant increases in sensitivity to mechanical indentation of the dura: their thresholds to dural indentation changed from 1.57 to 0.49 g (means, P < 0.0001), and the response magnitude to identical stimuli increased by two- to fourfold; 2) 80% of the neurons showed significant increases in cutaneous mechanosensitivity: their responses to brush and pressure increased 2.5- (P < 0.05) and 1. 6-fold (P < 0.05), respectively; 3) 75% of the neurons showed a significant increase in cutaneous thermosensitivity: their thresholds to slow heating of the skin changed from 43.7 +/- 0.7 to 40.3 +/- 0.7 degrees C (P < 0.005) and to slow cooling from 23.7 +/- 3.3 to 29.2 +/- 1.8 degrees C (P < 0.05); 4) dural receptive fields expanded within 30 min and cutaneous receptive fields within 2-4 h; and 5) ongoing activity developed in WDR and HT but not in LT neurons. Application of lidocaine to the dura abolished the response to dural stimulation but had minimal effect on the increased responses to cutaneous stimulation (suggesting involvement of a central mechanism in maintaining the sensitized state). Antidromic activation (current of <30 muA) of dura-sensitive neurons revealed projections to the hypothalamus, thalamus, and midbrain. These findings suggest that chemical activation and sensitization of dura-sensitive peripheral nociceptors could lead to enhanced responses in central neurons and that this central sensitization therefore could result in extracranial tenderness (mechanical and thermal allodynia) in the absence of extracranial pathology. The projection targets of these neurons suggest a possible role in mediating the autonomic, endocrine, and affective symptoms that accompany headaches.

Cervical Referral of Head Pain in Migraineurs: Effects on the Nociceptive Blink Reflex

“…[15][16][17][18] Recently, the R2 component of the nBR was examined before and after unilateral GON blocks where it was found that the R2 latency increased and area under the curve (AUC) decreased after GON blockade. 13,14 This result provides empirical evidence for a functional influence on trigeminal nociceptive inputs from cervical afferents. Conceivably, occipital activation of the TCN represents the cervicogenic equivalent to application of an "inflammatory soup" onto the dura that has been shown to induce central sensitization and ensuing increased sensitivity to trigeminal inputs.…”

“…12 Further support was provided by modulation of the nociceptive blink reflex (nBR) following blockade of the GON. 13,14 The nBR is a trigeminofacial brainstem reflex and has been established as a valid technique for assessing central trigeminal transmission. [15][16][17][18] Recently, the R2 component of the nBR was examined before and after unilateral GON blocks where it was found that the R2 latency increased and area under the curve (AUC) decreased after GON blockade.…”

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

“…A platinum-coated tungsten microelectrode (impedance 4-6 MΩ) was lowered repeatedly into the medullary dorsal horn in search for a target unit. At the end of the experiment, a small lesion was produced at the recording site and its localization in the dorsal horn was determined postmortem using histological analysis as described before (Burstein et al, 1998). Single-unit activity in the trigeminal ganglion (group 3) was recorded using a platinum-coated tungsten microelectrode (impedance 500 KΩ) lowered through a 2-mm circular opening that was drilled in the left parietal bone, about 2 mm caudal to the Bregma suture and 2 mm left to the midline.…”

“…A neuron was identified as a meningeal nociceptor if it responded with a constant latency to electrical stimuli from the dura but not to noxious mechanical stimuli from adjacent structures (i.e., pericranial muscles, cornea, vibrissae and ophthalmic skin). Conduction velocity was calculated using the shortest response latency to electrical stimulation of the dura which was divided by 12.5 mm -the distance between the trigeminal ganglion and the stimulation site in the dura (Burstein et al, 1998). Based on conduction velocity, neurons were classified a C-units (≤1.5 m/sec) or Aδ-units (>1.5 m/sec).…”

Pain Free Efficacy of Sumatriptan in the Early Treatment of Migraine

“…During a migraine attack these central sensory neurons may become sensitized, ('central sensitization') resulting in further pain progression. 12 This hypothesized pathophysiologic mechanism is a valid rationale for the early treatment of migraine pain.…”