R. Burstein et al., CHEMICAL-STIMULATION OF THE INTRACRANIAL DURA INDUCES ENHANCED RESPONSES TO FACIAL STIMULATION IN BRAIN-STEM TRIGEMINAL NEURONS, Journal of neurophysiology, 79(2), 1998, pp. 964-982
Chemical activation and sensitization of trigeminal primary afferent n
eurons innervating the intracranial meninges have been postulated as p
ossible causes of certain headaches. This sensitization, however, cann
ot explain the extracranial hypersensitivity that often accompanies he
adache. The goal of this study was to test the hypothesis that chemica
l activation and sensitization of meningeal sensory neurons can lead t
o activation and sensitization of central trigeminal neurons that rece
ive convergent input from the dura and skin. This hypothesis was inves
tigated by recording changes in the responsiveness of 23 [16 wide-dyna
mic range (WDR), 5 high threshold (HT), and 2 low threshold (LT)] dura
-sensitive neurons in nucleus caudalis to mechanical stimulation of th
eir dural receptive fields and to mechanical and thermal stimulation o
f their cutaneous receptive fields after local application of inflamma
tory mediators or acidic agents to the dura. Responses to brief chemic
al stimulation were recorded in 70% of the neurons most were short, la
sting the duration of the stimulus only. Twenty minutes after chemical
stimulation of the dura, the following changes occurred: 1) 95% of th
e neurons showed significant increases in sensitivity to mechanical in
dentation of the dura: their thresholds to dural indentation changed f
rom 1.57 to 0.49 g (means, P < 0.0001), and the response magnitude to
identical stimuli increased by two-to four fold, 2) 80% of the neurons
showed significant increases in cutaneons mechanosensitivity: their r
esponses 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 i
ncrease in cutaneous thermosensitivity: their thresholds to slow heati
ng 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 cu
taneous receptive fields within 2-4 h; and 5) ongoing activity develop
ed in WDR and HT but not in LT neurons. Application of lidocaine to th
e dura abolished the response to dural stimulation but had minimal eff
ect on the Increased responses to cutaneous stimulation (suggesting in
volvement of a central mechanism in maintaining the sensitized stale).
Antidromic activation (current of <30 mu A) of dura-sensitive neurons
revealed projections to the hypothalamus, thalamus, and midbrain. The
se 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 re
sult 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.