Brain, Vol. 123, No. 9, 1830-1837,
September 2000
© 2000 Oxford University Press
Nitric oxide-induced headache in patients with chronic tension-type headache
Department of Neurology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark
Correspondence to:
Messoud Ashina, Department of Neurology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Copenhagen, Denmark E-mail: ashina{at}dadlnet.dk
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and methodsResultsDiscussionReferences |
|---|
An experimental model of headache offers unique possibilities to study the mechanisms responsible for head pain. Using the glyceryl trinitrate [GTN; nitric oxide (NO) donor] model of experimental headache, we studied the intensity, quality and time profile of headache after infusion of GTN in 16 patients with chronic tension-type headache and in 16 healthy controls. Subjects were randomized to receive intravenous infusion of GTN (0.5 µg/kg per minute for 20 min) or placebo on two headache-free days separated by at least 1 week. Headache intensity was measured on a 10-point verbal rating scale during 2 h of observation and for the next 10 h after discharge from hospital. The primary endpoints were the difference between the area under the curve (AUC—intensities x duration) for headache recorded on the day of GTN treatment and on the day of placebo treatment in patients, and in patients and controls on the days of GTN treatment. In patients, the AUC on a GTN day [2221 (1572–3704); median with quartiles in paren- theses], was significantly greater than on a placebo day [730 (60–1678), P = 0.008]. On the GTN day, the AUC in patients [2221 (1572–3704)] was significantly higher than in controls [43 (0–972), P = 0.0001]. In patients, peak pain intensity occurred 8 h after infusion of GTN, whereas in controls it occurred 20 min after the start of infusion. The present study demonstrates that an NO-induced biphasic response with an immediate and a delayed headache is common to chronic tension-type headache and migraine. Furthermore, the NO-induced delayed headache has the characteristics of the primary headache disorder. This suggests that NO contributes to the mechanisms of several types of primary headaches and that NO-related central sensitization may be an important common denominator in the pain mechanisms of primary headaches.
tension-type headache; nitric oxide; central sensitization; glyceryl trinitrate; primary headaches
AUC = area under the curve; IHS = International Headache Society; GTN = glyceryl trinitrate; NO = nitric oxide; NOS = nitric oxide synthase
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Nitric oxide (NO) plays a key role in migraine (Thomsen and Olesen, 1998
) and cluster headache (Fanciullacci et al., 1997). This freely diffusible molecule is involved in a variety of biological functions, including neurotransmission (Garthwaite and Boulton, 1995). NO also contributes to sensory transmission in the peripheral and central nervous system (Aley et al., 1998; Wu et al., 1998). We have observed previously that systemic administration of the NO donor glyceryl trinitrate (GTN) may induce strong immediate headache in patients with episodic tension-type headache compared with healthy subjects (Olesen et al., 1993), and we demonstrated recently that nitric oxide synthase (NOS) inhibition has an analgesic effect in patients with chronic tension-type headache (Ashina et al., 1999). It remains unknown, however, whether NO induces more intense headache in patients with chronic tension-type headache than in healthy controls and, if so, what the characteristics and time profile of such headache might be. In the present study we recorded the intensity, quality and time profile of headache after infusion of the NO donor GTN in patients with chronic tension-type headache and compared GTN-induced headache in patients and healthy controls. |
Material and methods |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Subjects
We recruited 16 patients with a diagnosis of chronic tension-type headache according to the criteria of the International Headache Society (IHS) (Headache Classification Committee, 1988
) (headache frequency 
15 days per month for 6 months) from the out-patient headache clinic at Glostrup Hospital (Table 1). All patients underwent a general physical examination and a neurological examination and completed a diagnostic headache diary (Russell et al., 1992) during a 4-week run-in period. Exclusion criteria were: history of migraine or any other type of primary headaches; any kind of daily medication (including prophylactic headache therapy but not oral contraceptives); excessive use of analgesics (corresponding to >2 g aspirin/day); serious somatic or psychiatric diseases, including depression (Hamilton depression score 17) (Hamilton, 1960).
|
Sixteen healthy volunteers served as controls (Table 1
). The controls never had migraine and had fewer than 12 headache days per year. All subjects gave written consent to participation in the study, which was approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki.
Procedures
In a double-blind, placebo-controlled crossover design, the patients and controls were allocated randomly to receive GTN at 0.5 µg/kg per minute or placebo (isotonic saline) on 2 days separated by at least 1 week. Medical staff not involved in the study performed the randomization and prepared the study drug. The randomization code remained in the hospital during the study and was not available to the investigators until the study was complete. All subjects, who had been completely headache-free for at least 12 h before the examination, were examined on days without headache at 09.00 hours. The subjects were not allowed to take any kind of analgesic for 24 h before the examination. GTN or placebo was infused over 20 min into an antecubital vein, as allocated by the randomization code. The study solutions looked the same. The following measurements were recorded at baseline and every 5 min until 60 min after the start of infusion and then every 15 min until 120 min after the start of infusion: headache intensity on a verbal rating scale (0–10: 0, no headache; 5, moderate headache; 10, worst imaginable headache); blood pressure and pulse rate. The verbal rating scale was chosen because this method of pain measurement has been used in previous studies of GTN-induced headache in migraineurs (Thomsen et al., 1994). Twelve-lead ECG was performed before examination. Any adverse events were recorded. Subjects with headache 120 min after the start of infusion were allowed to take rescue medication. All subjects were asked to record details of the following on a diary card 4, 8, 12, 16, 20 and 24 h after start of infusion: headache location; headache intensity (verbal rating scale); headache quality and aggravation by physical activity; associated symptoms; any medication taken; and adverse events. The diary cards were mailed to the clinic after each treatment.
Data analysis and statistics
Results are presented as median with quartiles in parentheses. The primary endpoint was the difference between the area under the headache curve (AUC—intensity x duration) recorded over 12 h of observation on an active day and on a placebo day in patients. The secondary endpoint was the difference between the AUC recorded on the active day in patients and controls. The AUC was calculated according to the trapezium rule (Matthews et al., 1990). The difference between the AUCs recorded on an active day and on a placebo day within patients and controls was compared by the use of the Wilcoxon signed ranks test. The difference between the AUCs recorded on an active day in patients and controls was compared by the use of the Mann–Whitney test. To assess changes in blood pressure and pulse rate in patients over the first 60 min after active treatment or placebo, we used the paired samples t-test. Five per cent was accepted as the level of significance. All data were analysed with SPSS® version 7.5.1 software (SPSS Inc., Chicago, Ill., USA).
|
Results |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
GTN and placebo infusions in patients
The AUC on a GTN day [2221 (1572–3704)], was significantly higher than on a placebo day [730 (60–1678)] (P = 0.008) (Fig. 1
). During GTN infusion, 15 out of 16 patients developed immediate headache, with peak intensity 20 min after the start of infusion (Table 2 and Fig. 1). One patient (patient 16) developed a migraine-like headache lasting ~15 min (Table 2). During placebo infusion, three out of 16 patients developed a bilateral, mild (range 2–3 on the verbal rating scale), pressing headache without associated symptoms. After GTN infusion, 15 out of 16 patients developed a delayed headache (Table 2) with peak intensity 8 h after the start of infusion (Fig. 1). In 13 patients the headache fulfilled IHS criteria for tension-type headache, while two patients (patients 14 and 15) developed a headache which fulfilled the diagnostic criteria for migraine without aura. Eight patients took simple analgesics as a rescue medication on the GTN day. After placebo infusion, 11 patients reported a delayed headache. The headache intensity of these patients reached its peak 10 h after the start of infusion (Fig. 1). None of the patients developed a migraine headache. Two patients took simple analgesics as a rescue medication on the placebo day.
|
|
GTN and placebo infusions in controls
The AUC on the GTN day [43 (0–972)] was significantly higher than on the placebo day [0 (0–0)] (P = 0.008) (Fig. 2). During the GTN infusion, nine out of 16 controls developed a headache without associated symptoms. The headache intensity reached its peak 20 min after the start of infusion. After discharge from hospital, six out of 16 controls developed a delayed headache (Table 3). One subject (subject 3) developed a headache, which fulfilled the IHS diagnostic criteria for migraine without aura. On the placebo day, none of the subjects developed a headache during the infusion or in the 12 h following infusion.
|
|
GTN infusion in patients versus controls
The AUC in patients [2221 (1572–3704)] was significantly higher than that in controls [43 (0–972)] (P = 0.0001).
GTN infusion in patients with pressing headache versus controls
When the five patients whose usual headache quality was throbbing were excluded, the remaining 11 patients, whose headache was of a pressing quality, still had a significantly higher response to GTN [2003 (1410–2873)] than 16 controls [43 (0–972)] (P = 0.0001). In these patients, the AUC on the GTN day [2003 (1410–2873)] was also significantly higher than on a placebo day [660 (0–1348)] (P = 0.02). None of these patients developed a migraine headache.
Immediate and delayed headache in patients
The AUC recorded over the initial 120 min (immediate headache) observation on the GTN day [171 (31–426)] was significantly higher than on the placebo day [0 (0–91)] (P = 0.02). The AUC recorded from 120 min to 12 h (delayed headache) after infusion on the GTN day [2108 (1541–3465)] was significantly higher than on the placebo day [720 (60–1410)] (P = 0.008).
Haemodynamics in patients
The mean arterial blood pressure (MAP) decreased significantly during treatment with GTN compared with placebo (P = 0.01) (Fig. 3). Patients were clinically unaffected by these changes. There was no difference in pulse rate during treatment with GTN and placebo (P = 0.50) (Fig. 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Previous studies of experimental headache in tension-type headache
In 1980, Krabbe and Olesen infused histamine intravenously into patients with chronic tension-type headache (Krabbe and Olesen, 1980
). The patients developed pressure-like, constant headache with an intensity intermediate between those in migraine patients and healthy controls. It was not reported whether the patients developed delayed headache. Histamine presumably causes production of NO via an endothelial H1 receptor (Lassen et al., 1996). In another study, by Olesen and colleagues, the exogenous NO donor GTN was given intravenously to 17 migraineurs, nine patients with episodic tension-type headache and 17 healthy control subjects (Olesen et al., 1993). Seven out of nine patients developed a nitroglycerin-induced headache (immediate) with intensity and duration intermediate between those of migraineurs and healthy controls.
Present results in relation to findings in migraine
It was important to compare the GTN response with the placebo response in patients with chronic tension-type headache, because a high proportion of these patients were expected to develop their usual headache in the experimental period. In the present study, 15 out of 16 patients developed a delayed headache with mean peak intensity 8 h after the start of GTN infusion. Eleven patients developed a delayed headache of low intensity with a maximum 10 h after placebo infusion. This was likely to represent their usual headache. Both the immediate (0–2 h observation) and the delayed (2–12 h observation) headache were significantly stronger on the GTN day than on the placebo day. In controls, GTN induced a headache during infusion, which rapidly disappeared after the infusion had stopped. Interestingly, the time profile of the GTN-induced headache in patients with chronic tension-type headache was strikingly similar to the time profile of GTN-induced headache in patients with migraine without aura (Thomsen et al., 1994). Thus, patients with migraine without aura developed an immediate headache during GTN infusion and a delayed headache fulfilling the IHS criteria for migraine several hours after the infusion was stopped. Peak intensity occurred 5.5 h after the infusion was stopped. The characteristics of the delayed headache in chronic tension-type headache were, however, different from those in patients with migraine. Thus, 80% of migraine patients developed migraine without aura after infusion of GTN (Thomsen et al., 1994), whereas only 13% of patients with chronic tension-type headache did so in the present study. The other 87% developed a tension-type headache. None of our patients had previously experienced migraine fulfilling the IHS criteria. To exclude the possibility that previous migraine had been overlooked, patients who had previously experienced throbbing headaches were analysed separately. Two patients who developed migraine headache were in this group, but the three others did not develop migraine. Furthermore, patients with exclusively pressing pain in the past also developed a significantly stronger headache during and after GTN infusion than controls. Our results indicate that patients with chronic tension-type headache similar to that of patients with migraine are supersensitive to NO, and that the majority of patients in both groups develop their usual headache several hours after the infusion of GTN.
Possible mechanisms of immediate and delayed headache
The most important finding in the present study was that systemic administration of the NO donor GTN in patients with chronic tension-type headache, as in migraineurs, resulted in a biphasic nociceptive response with a headache peak during infusion (immediate headache), a reduction in headache intensity for ~1.5 h (intermediate phase), and a second and more pronounced headache peak several hours later (delayed headache). We suggest that a direct effect of NO on perivascular sensory afferents and/or NO-induced arterial dilatation are responsible for the immediate headache and that enhanced central sensitization at the spinal/trigeminal level is responsible for the delayed headache.
NO evokes pain in humans when injected paravascularly or perfused through a vascularly isolated segment of a hand vein (Holthusen and Arndt, 1995). These findings suggest that NO may directly activate or sensitize nociceptors around blood vessels. Intravenous infusion of GTN (0.5 µg/kg per minute) over 20 min induces dilatation of the middle cerebral artery in healthy subjects (Iversen et al., 1989) and in migraineurs and patients with episodic tension-type headache (Thomsen et al., 1993). In these studies the dilatation lasted at least until 1 h after GTN infusion had stopped (Iversen et al., 1989; Thomsen et al., 1993) and 3 h in another study (Lassen et al., 1996). Furthermore, vasodilatation of the middle meningeal artery in rats increases the firing rate in the trigeminal nucleus caudalis (Cumberbatch et al., 1999). Collectively, these studies suggest that immediate headache after infusion of GTN in patients with chronic tension-type headache may originate in NO-induced activation or sensitization of sensory nerves around the cephalic/extracephalic arteries or from NO-induced arterial dilatation, or both.
Basic pain research has demonstrated that central sensitization, i.e. increased excitability of neurones in the CNS, generated by prolonged nociceptive input from the periphery, plays an important role in the pathophysiology of chronic pain (Woolf, 1983; Hu et al., 1992; Woolf and Doubell, 1994). NO is released in the spinal cord during central sensitization, and prolonged elevation of NO within the spinal dorsal horn is important in maintaining the central sensitization (Lin et al., 1999). While inhibition of NOS has been shown to reduce central sensitization in animal models of persistent pain (Haley et al., 1992; Hao and Xu, 1996; Mao et al., 1997), nociceptive responses in these models are enhanced by NO donors (Kitto et al., 1992; Coderre and Yashpal, 1994). Furthermore, it was reported that inhibition of NOS markedly reduces Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus (Hoskin et al., 1999). Interestingly, in animals, formalin-induced tissue injury results in a biphasic nociceptive response (Coderre and Yashpal, 1994) similar to that observed in the present study. The second pain phase may be caused by central sensitization, and NOS inhibition reduces pain only in this phase (Coderre and Yashpal, 1994).
Recent clinical studies suggest that central sensitization at the spinal/trigeminal level caused by nociceptive input from pericranial myofascial tissues may play an important role in chronic tension-type headache (Bendtsen et al., 1996; Jensen et al., 1998). Furthermore, we demonstrated recently that NOS inhibition has an analgesic effect in chronic tension-type headache, probably due to reduction of central sensitization (Ashina et al., 1999). Studies in rats and in humans have shown that after intravenous administration of GTN very little drug remains in the blood, and that the majority of the GTN is distributed to the tissues (Sorkin et al., 1984). In anaesthetized cats, intravenous infusion of GTN (0.25 µg/kg per minute over 20 min) induced a prolonged (60 min) increase in NO in the parenchyma of the brain (Read et al., 1997), and a prolonged increase in the level of NO in the spinal dorsal horn was demonstrated during central sensitization (Wu et al., 1998). These data indicate that infusion of GTN may result in the storage and subsequent liberation of NO or may trigger endogenous NO production in the CNS, thereby increasing the sensitization of nociceptive pathways in the CNS.
Sustained NO-induced vascular nociception may lead to central sensitization and the subsequent convergence of nociceptive input from blood vessels and myofascial tissue. As mentioned earlier, NO may activate or sensitize nociceptors around blood vessels directly or by dilatation. Dilatation of the meningeal blood vessels in rats causes sensitization of central trigeminal neurones and facilitation of convergent sensory responses (Cumberbatch et al., 1999). Interestingly, trigeminal neurones became maximally sensitized after the peak increase in vessel diameter and the increased excitability exceeded the period of vasodilatation (Cumberbatch et al., 1999). It is, therefore, possible that excessive vascular nociception caused by GTN may gradually augment the sensitizing effect of pre-existing myofascial input in chronic tension-type headache sufferers (Olesen, 1991).
The questions of why patients with chronic tension-type headache and patients with migraine develop delayed headache of greater intensity with different characteristics and why most healthy subjects develop no delayed headache or only a minor one are important. The most likely explanation is that pre-existing facilitation of distinct nociceptive central pathways in chronic tension-type headache sufferers (myofascial pathways) and migraineurs (vascular pathways) may be enhanced by NO-induced central sensitization. This could explain why the delayed headache fulfilled tension-type headache criteria in patients with chronic tension-type headache and migraine criteria in migraineurs. This could also explain why NO does not induce strong delayed headache in healthy subjects when no pre-existing sensitization is present.
In conclusion, the present study provides important information about NO mechanisms in chronic tension-type headache. It is suggested that NO-induced delayed headache in patients with chronic tension-type headache is due to augmentation of pre-existing central sensitization. Moreover, our results indicate that NO contributes to the mechanisms of several types of primary headaches and that NO-related central sensitization may be an important common denominator in the pain mechanisms of primary headaches, although their basic pathophysiological mechanisms are different.
Acknowledgements
We wish to thank Mrs Hanne Andresen for skilful technical assistance. The study was supported financially by the University of Copenhagen.
|
References |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Aley KO, McCarter G, Levine JD. Nitric oxide signaling in pain and nociceptor sensitization in the rat. J Neurosci 1998; 18: 7008–14.
Ashina M, Lassen LH, Bendtsen L, Jensen R, Olesen J. Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial. Lancet 1999; 353: 287–9.[Web of Science][Medline]
Bendtsen L, Jensen R, Olesen J. Qualitatively altered nociception in chronic myofascial pain. Pain 1996; 65: 259–64.[Web of Science][Medline]
Coderre TJ, Yashpal K. Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in the rat formalin pain model. Eur J Neurosci 1994; 6: 1328–34.[Web of Science][Medline]
Cumberbatch MJ, Williamson DJ, Mason GS, Hill RG, Hargreaves RJ. Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Br J Pharmacol 1999; 126: 1478–86.[Web of Science][Medline]
Fanciullacci M, Alessandri M, Sicuteri R, Marabini S. Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain 1997; 120: 283–8.
Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. [Review]. Annu Rev Physiol 1995; 57: 683–706.[Web of Science][Medline]
Haley JE, Dickenson AH, Schachter M. Electrophysiological evidence for a role of nitric oxide in prolonged chemical nociception in the rat. Neuropharmacology 1992; 31: 251–8.[Web of Science][Medline]
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.
Hao J, Xu X. Treatment of chronic allodynia-like response in spinally injured rats: effects of systemically administered nitric oxide synthase inhibitors. Pain 1996; 66: 313–9.[Web of Science][Medline]
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 Suppl 7: 1–96.
Holthusen H, Arndt JO. Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans. J Physiol (Lond) 1995; 487: 253–8.
Hoskin KL, Bulmer DC, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci Lett 1999; 266: 173–6.[Web of Science][Medline]
Hu JW, Sessle BJ, Raboisson P, Dallel R, Woda A. Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brain-stem neurones. Pain 1992; 48: 53–60.[Web of Science][Medline]
Iversen HK, Holm S, Friberg L. Intracranial hemodynamics during intravenous nitroglycerin infusion [abstract]. Cephalalgia 1989; 9 Suppl 10: 84–5.
Jensen R, Bendtsen L, Olesen J. Muscular factors are of importance in tension-type headache. Headache 1998; 38: 10–7.[Web of Science][Medline]
Kitto KF, Haley JE, Wilcox GL. Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 1992; 148: 1–5.[Web of Science][Medline]
Krabbe AA, Olesen J. Headache provocation by continuous intravenous infusion of histamine. Clinical results and receptor mechanisms. Pain 1980; 8: 253–9.[Web of Science][Medline]
Lassen LH, Thomsen LL, Kruuse C, Iversen HK, Olesen J. Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine. Support for the NO-hypothesis of migraine. Eur J Clin Pharmacol 1996; 49: 335–9.[Web of Science][Medline]
Lin Q, Palecek J, Paleckova V, Peng YB, Wu J, Cui M, et al. Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol 1999; 81: 1075–85.
Mao J, Price DD, Zhu J, Lu J, Mayer DJ. The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat. Pain 1997; 72: 355–66.[Web of Science][Medline]
Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. BMJ 1990; 300: 230–5.
Olesen J. Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs. Pain 1991; 46: 125–32.[Web of Science][Medline]
Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. [Review]. Neuroreport 1993; 4: 1027–30.[Web of Science][Medline]
Read SJ, Smith MI, Hunter AJ, Parsons AA. Enhanced nitric oxide release during cortical spreading depression following infusion of glyceryl trinitrate in the anaesthetized cat. Cephalalgia 1997; 17: 159–65.[Web of Science][Medline]
Russell MB, Rasmussen BK, Brennum J, Iversen HK, Jensen RA, Olesen J. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 1992; 12: 369–74.[Web of Science][Medline]
Sorkin EM, Brogden RN, Romankiewicz JA. Intravenous glyceryl trinitrate (nitroglycerin). A review of its pharmacological properties and therapeutic efficacy. [Review]. Drugs 1984; 27: 45–80.[Web of Science][Medline]
Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia 1993; 13: 395–9.[Web of Science][Medline]
Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994; 1: 73–80.
Thomsen LL, Olesen J. Nitric oxide theory of migraine. [Review]. Clin Neurosci 1998; 5: 28–33.[Web of Science][Medline]
Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983; 306: 686–8.[Medline]
Woolf CJ, Doubell TP. (1994) The pathophysiology of chronic pain—increased sensitivity to low threshold A beta-fibre inputs. [Review]. Curr Opin Neurobiol 1994; 4: 525–34.[Medline]
Wu J, Lin Q, McAdoo DJ, Willis WD. Nitric oxide contributes to central sensitization following intradermal injection of capsaicin. Neuroreport 1998; 9: 589–92.[Web of Science][Medline]
Received February 10, 2000. Revised April 27, 2000. Accepted May 8, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Benoliel, J. Epstein, E. Eliav, R. Jurevic, and S. Elad Orofacial Pain in Cancer: Part I--Mechanisms Journal of Dental Research, June 1, 2007; 86(6): 491 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Levy and A. M. Strassman Modulation of Dural Nociceptor Mechanosensitivity by the Nitric Oxide-Cyclic GMP Signaling Cascade J Neurophysiol, August 1, 2004; 92(2): 766 - 772. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||