Recent animal experiments have shown that chronic medication exposure profoundly affects the function of several areas in the nervous system related to headache pathogenesis. These changes include upregulation of calcitonin gene-related peptide, substance P, and nitric oxide synthase in trigeminal ganglia; expansion of receptive field and decreased nociceptive threshold of central trigeminal neurons; decrease in diffuse noxious inhibitory control; and increased susceptibility to develop cortical spreading depression (CSD). These changes indicate an increase in excitability of cortical and trigeminal neurons. The neuronal hyperexcitability may be the result of derangement of a central, possibly serotonin (5-HT)-dependent, modulating control system. Experiments with animals with low 5-HT showed that the processes of CSD and trigeminal nociception are enhanced in this condition. Derangement in the central 5-HT-dependent modulating system as a result of chronic medication use may underlie the chronification of headache as observed in patients with medication-overuse headache.
Hippocampal long-term potentiation (LTP) of excitatory synaptic transmission has been regarded as a cellular model of learning and memory. Its induction is regulated by many functional molecules at synapses, including the neuropeptide nociceptin, which is identified as an endogenous ligand for the orphan opioid receptor. Mutant mice lacking the receptor exhibit enhanced LTP and hippocampusdependent memory formation; however, the precise molecular and cellular mechanism is largely unknown. Here, we show that LTP in the hippocampal CA1 region is inhibited by nociceptin synaptically released from interneurons by tetanic stimulation. This endogenous nociceptin downregulates the excitability of pyramidal cells by the hyperpolarization induced by the activation of K ϩ channels, which are the common target shared with GABA B receptors, although the mode of action is considerably different. Interestingly, the modulation of LTP by endogenous nociceptin is not observed when theta-burst stimulation is used instead of tetanic stimulation, suggesting that relatively longer high-frequency synaptic activation is required for the release of endogenous nociceptin. These results indicate that, in addition to GABA, nociceptin released from interneurons by their high-frequency activation is a novel endogenous neuromodulator that negatively regulates LTP induction in the hippocampus through direct modulation of pyramidal cells.
Parkinson’s disease (PD) is associated with dysfunction of monoamine neurotransmitter systems. We investigated changes in the levels of monoamine and their metabolites in PD patients, together with their association to clinical profiles. PD patients and age-matched control subjects (n = 40 per group) were enrolled. Using high-performance liquid chromatography (HPLC) with an electrochemical detector, levels of monoamines (dopamine, DA; norepinephrine, NE; epinephrine, EPI; and serotonin, 5-HT) were measured in plasma, while the metabolites (homovanillic acid, HVA; vanillylmandelic acid, VMA; and 5-hydroxyindoleacetic acid, 5-HIAA) were measured in urine. Plasma DA level was not significantly different between PD and control groups. PD patients had significantly higher plasma NE but lower EPI and 5-HT levels. PD patients had a significantly higher HVA/DA ratio and lower VMA/NE ratio than control subjects, while the 5-HIAA/5-HT ratio was not different between the groups. Regarding the association between monoamine levels and clinical profiles, the DA level had a negative relationship with disease duration and the 5-HT level had a negative relationship with severity of motor impairment. These findings emphasized the involvements of several neurotransmission systems and their association with clinical profiles in PD patients, demonstrated by quantification of monoamine levels in peripheral body fluids. This could benefit appropriate pharmacological treatment planning in respect of monoamine changes and might also help predict subsequent clinical symptoms.
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