Anan Srikiatkhachorn

Effect of Chronic Analgesic Exposure on the Central Serotonin System: A Possible Mechanism of Analgesic Abuse Headache

Objective.–To investigate the effects of chronic analgesic exposure on the central serotonin system and the relationship between the serotonin system and the analgesic efficacy of nonnarcotic analgesics.

Serotonin depletion, cortical spreading depression, and trigeminal nociception.

Background.—The attack of migraine has been observed to be associated with low level of serotonin (5‐HT). Although the mechanism underlying this relationship is still unclear, change in cortical excitability or susceptibility of trigeminal system is a possible explanation.

5‐HT2A Receptor Activation and Nitric Oxide Synthesis: A Possible Mechanism Determining Migraine Attacks

Objective.—To determine the effect of the 5‐HT2A receptor in control of spinal nociception, cerebral circulation, and nitric oxide synthase (nNOS) expression in trigeminovascular neurons.

Prevalence and Clinical Features of Chronic Daily Headache in a Headache Clinic

Although chronic daily headache is regarded as a syndrome encountered in headache clinics, clinical characteristics have only rarely been studied and the condition has not been documented in Thailand. To investigate the prevalence as well as clinical features of chronic daily headache in Thai patients, 220 patients visiting Chulalongkorn Headache Clinic were examined. Sixty cases (27.3%) were diagnosed as suffering from chronic daily headache (male to female ratio, 1:5.7).

Acetaminophen-induced antinociception via central 5-HT2A receptors

Acetaminophen is one of the most widely used analgesic drugs. Although the mechanism of analgesic action of acetaminophen is still not known, the involvement of the central serotonin (5-hydroxytryptamine: 5-HT) system is one possibility. In the present study, we examined the antinociceptive effect of acute and chronic intraperitoneally (i.p.) administered acetaminophen by tail flick latency measurements in the rat. A significantly increased tail flick latency was observed in acute and 15-day acetaminophen-treated rats, but not in 30-day acetaminophen-treated rats, at a dose of 400 mg/kg/day. To investigate the plasticity of receptors at postsynaptic membrane, we conducted a series of experiments by radioligand binding method on frontal cortex and brainstem membrane. The technique involved radioligand binding with [phenyl-4-3H]spiperone and ketanserin for studying 5-HT(2A) receptor characteristics. A significant decrease in the maximum number of 5-HT(2A) binding sites (Bmax) was demonstrated in all treatment groups with acetaminophen 300 and 400 mg/kg on frontal cortex membrane, whereas the value of the dissociation equilibrium constant (Kd) remained unchanged. The down-regulation of 5-HT(2A) binding sites in frontal cortex was of a lesser magnitude after 30 days of treatment and the tail flick latency was as in the control animals. These results suggest that down-regulation of 5-HT(2A) receptor in response to 5-HT release is a major step in the mechanism underlying analgesia produced by this agent. On the contrary, chronic use of acetaminophen may result in 5-HT depletion, which in turn produces re-adaptation of postsynaptic 5-HT(2A) receptors. These data provide further evidence for a central 5-HT-dependent antinociceptive effect of acetaminophen.

Derangement of Serotonin System in Migrainous Patients With Analgesic Abuse Headache: Clues From Platelets

Accumulating evidence indicates that serotonin (5‐HT) may be involved in the process of analgesic‐induced headache transformation. In order to clarify this hypothesis, we investigated the 5‐HT system in migraine patients with analgesic abuse headache by using platelets as a neuronal model. Our results revealed a significant decrease in platelet 5‐HT content in these patients compared to migraine patients and nonheadache controls (179.24 ± 10.18, 451.22 ± 14.35, and 480.22 ± 13.98 ng/109 platelets, respectively; P<0.001). This biochemical result was well correlated with a significant decrease (P

Up‐regulation of 5‐HT2 Serotonin Receptor: A Possible Mechanism of Transformed Migraine

SYNOPSIS

Plasticity of 5-HT2A serotonin receptor in patients with analgesic-induced transformed migraine

Chronic drug exposure can induce a significant change in neurotransmitter receptor systems and is possibly involved in the pathogenesis of drug‐induced neurological disorders. Abuse of analgesics is known to induce deterioration in headache status in patients with primary headaches, especially migraine. To assess the possibility of 5‐HT2A serotonin receptor plasticity in this condition, we investigated receptor binding on the platelet membrane in patients with analgesic‐induced transformed migraine, patients with migraine, and nonheadache controls. Various concentrations of [3H]‐spiperone (0.4 to 12 nmol) was used as a radioligand, and ketanserin was used to determine nonspecific binding. A lower maximal number of receptors (Bmax) was observed in patients with migraine as compared to patients with transformed migraine, and controls (467 ± 58, 708 ± 36, and 786 ± 64 fmol/mg protein, respectively, P<0.01); whereas the value of the dissociation equilibrium constant (Kd) remained unchanged (1.72 ± 0.16, 1.41 ± 0.13, and 1.25 ± 0.21 nmol for patients with migraine, patients with transformed migraine, and nonheadache controls, respectively). A significant decrease in Bmax value was observed in patients with transformed migraine after 4 weeks of analgesic withdrawal (770 ± 25 and 345 ± 31 fmol/mg protein, P<0.001), whilst no significant change in Kd value was observed (1.95 ± 0.12 and 2.47 ± 0.30 nmol, respectively). These findings indicate that 5‐HT2A serotonin receptor system is altered in patients with transformed migraine with analgesic overuse. Such receptor plasticity may be an important step in the pathogenic mechanism of transformed migraine.

Involvement of Pro‐Nociceptive 5‐HT2A Receptor in the Pathogenesis of Medication‐Overuse Headache

(Headache 2010;50:185‐197)

Cortical hyperexcitability and mechanism of medication-overuse headache

The present study was conducted to determine the effect of acute (1 h) and chronic (daily dose for 30 days) paracetamol administration on the development of cortical spreading depression (CSD), CSD-evoked cortical hyperaemia and CSD-induced Fos expression in cerebral cortex and trigeminal nucleus caudalis (TNC). Paracetamol (200 mg/kg body weight, intraperitonealy) was administered to Wistar rats. CSD was elicited by topical application of solid KCl. Electrocorticogram and cortical blood flow were recorded. Results revealed that acute paracetamol administration substantially decreased the number of Fos-immunoreactive cells in the parietal cortex and TNC without causing change in CSD frequency. On the other hand, chronic paracetamol administration led to an increase in CSD frequency as well as CSD-evoked Fos expression in parietal cortex and TNC, indicating an increase in cortical excitability and facilitation of trigeminal nociception. Alteration of cortical excitability which leads to an increased susceptibility of CSD development can be a possible mechanism underlying medication-overuse headache.