Yan-Juan Pan

The interaction between the oxytocin and pain modulation in headache patients

Oxytocin (OXT), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood-brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of OXT to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that OXT in the central nervous system rather than the blood circulation plays an important role in rat pain modulation. The communication tried to investigate the interaction between the OXT and pain modulation in Chinese patients with headache to understand the OXT effect on human pain modulation. The results showed that (1) intranasal OXT could relieve the human headache in a dose-dependent manner; (2) OXT concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients in relation with the pain level; and (3) there was a positive relationship between plasma and CSF OXT concentration in headache patients. The data suggested that intranasal OXT, which was delivered to the central nervous system through olfactory region, could treat human headache and OXT might be a potential drug of headache relief by intranasal administration.

Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides.

Periaqueductal gray (PAG) plays a very important role in pain modulation through endogenous opiate peptides including leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek), β-endorphin (β-Ep) and dynorphin A(1-13) (DynA(1-13)). Our pervious study has demonstrated that intra-PAG injection of oxytocin (OXT) increases the pain threshold, and local administration of OXT receptor antagonist decreases the pain threshold, in which the antinociceptive role of OXT can be reversed by pre-PAG administration of OXT receptor antagonist. The experiment was designed to investigate the effect of OXT on endogenous opiate peptides in the rat PAG during the pain process. The results showed that (1) the concentrations of OXT, L-Ek, M-Ek and β-Ep, not DynA(1-13) in the PAG perfusion liquid were increased after the pain stimulation; (2) the concentrations of L-Ek, M-Ek and β-Ep, not DynA(1-13) in the PAG perfusion liquid were decreased by the OXT receptor antagonist; (3) the increased pain threshold induced by the OXT was attenuated by naloxone, an opiate receptor antagonist; and (4) the concentrations of L-Ek, M-Ek and β-Ep, not DynA(1-13) in the PAG perfusion liquid were increased by exogenous OXT administration. The data suggested that OXT in the PAG could influence the L-Ek, M-Ek and β-Ep rather than DynA(1-13) to participate in pain modulation, i.e. OXT in the PAG participate in pain modulation by influencing the L-Ek, M-Ek and β-Ep rather than DynA(1-13).

Oxytocin in the periaqueductal grey regulates nociception in the rat

Studies have demonstrated that oxytocin (OXT) plays important roles in pain modulation in the central nervous system, and there are OXT receptors in the periaqueductal grey (PAG). The experiment was designed to investigate the effect of OXT in the PAG on antinociception. The results showed that (1) intra-PAG injection of OXT increased the pain threshold, whereas the local administration of the high specific OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold in a dose-dependent manner; (2) Pain stimulation could elevate OXT concentration in the PAG perfusion liquid. The data suggested that OXT in the PAG was involved in the antinociceptive process through the OXT receptor.

Oxytocin in the rat caudate nucleus influences pain modulation.

Our previous studies have demonstrated that oxytocin (OXT) in the central nervous system plays a role in pain modulation. Many studies have found that caudate nucleus (CdN) enriches OXT and OXT receptors by the methods of historadioautograph and gene expression. The communication was designed to investigate OXT effect in the rat CdN on pain modulation. The results showed that (1) intra-CdN microinjection of OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold, whereas the local administration of OXT increased the pain threshold in a dose-dependent manner; (2) OXT receptor antagonist can attenuate the analgesic role induced intra-CdN administration of OXT; and (3) pain stimulation could increase OXT concentration in the CdN perfusion liquid. The data suggested that OXT in the CdN was involved in this pain process via OXT receptors.

The influence of psychological stress on arginine vasopressin concentration in the human plasma and cerebrospinal fluid

Psychological stress is strain affecting the intangible self, caused by problems in adaptation, perception, and emotions. Previous studies have demonstrated that arginine vasopressin (AVP) plays an important role in psychological stress. The goal of present study was to investigate the interaction between AVP release and cardiovascular functions by measuring AVP concentration and recording blood pressure or heart rate during psychological stress in human. The results showed that (1) psychological stress not only increased the systolic blood pressure, diastolic blood pressure and heart rate, but also elevated the cortisol and AVP concentration in both plasma and CSF in a stress level-dependent manner; (2) there was a positive relationship between plasma AVP concentration and systolic blood pressure, diastolic blood pressure, heart rate or plasma cortisol concentration; (3) there was also a positive relationship between AVP concentrations in plasma and CSF AVP. The data suggested that plasma AVP, which might come from the central nervous system, might influence the cardiovascular functions during psychological stress in human.

Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus.

Our previous study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of L-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of L-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP.

Effect of arginine vasopressin on the behavioral activity in the behavior despair depression rat model

Arginine vasopressin (AVP), a nonapeptide posterior hormone of the pituitary, is mainly synthesized and secreted in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). Large numbers of studies have reported that AVP plays a role in depression. The present study was to investigate by which level, brain or periphery, AVP affects the behavioral activity in the behavior despair depression rat model. The results showed that (1) either forced swimming or tail suspension significantly increased AVP concentration not only in the brain (PVN, SON, frontal of cortex, hippocampus, amygdala, lumber spinal cord) but also in the periphery (posterior pituitary and serum); (2) intraventricular injection (icv) of AVP decreased the animal immobility time, whereas V₁ receptor antagonist d(CH₂)₅Tyr(Me)AVP (icv) increased the animal immobility time in a dose-dependent manner not only in FST but also in TST, but the V₂ receptor antagonist d(CH₂)₅[D-Ile, Ile, Ala-NH₉]AVP did not change the animal immobility time in FST or TST; (3) V₁, not V₂ receptor antagonist could inhibit the animal immobility time decrease induced by AVP (icv); (4) neither AVP nor its receptor antagonist (including V₁ and V₂ receptor antagonist) influenced the animal immobility time in both FST and TST. The data suggested that AVP in the brain rather than the periphery played a role in the behavior despair depression by V₁, not V₂ receptors, which behavior despair might have a positive feedback effect on central AVP and blood AVP might have a negative feedback on central AVP in the depressive process.

Effect of intranasal arginine vasopressin on human headache.

Arginine vasopressin (AVP), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood-brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of AVP to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that AVP in the brain rather than the spinal cord and blood circulation plays an important role in rat pain modulation. For understanding the role of AVP on pain modulation in human, the communication tried to investigate the effect of intranasal AVP on human headache. The results showed that (1) AVP concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients, who related with the headache level; (2) there was a positive relationship between plasma and CSF AVP concentration in headache patients; and (3) intranasal AVP could relieve the human headache in a dose-dependent manner. The data suggested that intranasal AVP, which was delivered to the brain through olfactory region, could treat human headache and AVP might be a potential drug of pain relief by intranasal administration.

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the caudate nucleus to participate in pain modulation.

Arginine vasopressin (AVP), which is synthesized and secreted in the hypothalamic paraventricular nucleus (PVN), is the most important bioactive substance in the pain modulation. Our pervious study had shown that AVP plays an important role in pain modulation in caudate nucleus (CdN). The experiment was designed to investigate the source of AVP in CdN by the nucleus push-pull perfusion and radioimmunoassay. The results showed that: (1) pain stimulation increased the AVP concentration in the CdN perfusion liquid, (2) PVN decreased the effect of pain stimulation which was stronger in both sides than in one side of PVN cauterization; and (3) L-glutamate sodium would excited the PVN neurons by the PVN microinjection that could increase the AVP concentration in the CdN perfusion liquid. The data suggested that AVP in the CdN might come from the PVN in the pain process, i.e., AVP in the PVN might be transferred to the CdN to participate in the pain modulation.

Pharmacokinetics of diltiazem hydrochloride delay-onset sustained-release pellet capsules in healthy volunteers

Embora a farmacocinetica (PK) do cloridrato de diltiazem nas formas de comprimidos de liberacao imediata e capsulas de liberacao modificada em ensaios clinicos ja tenha sido relatada, a pesquisa da PK do cloridrato de diltiazem na forma de capsulas com peletes de liberacao retardada e sustentada ainda e muito importante. Neste trabalho, propusemos avaliar a farmacocinetica do cloridrato de diltiazem administrado atraves desta nova forma farmaceutica em voluntarios chineses sadios, assim como a influencia da ingestao de alimentos neste perfil farmacocinetico. Foi realizado um ensaio clinico aberto, randomizado e paralelo em 36 voluntarios, que receberam dose oral unica de 90 mg, 180 mg ou 270 mg e dose multiplas (90 mg/d × 6 d) pela mesma via de administracao. Para avaliar o efeito da ingestao de alimentos sobre a PK do diltiazem foi realizada a administracao de dose unica (360 mg) em 24 voluntarios chineses sadios. A concentracao plasmatica do diltiazem foi determinada por Cromatografia Liquida de Alta Eficiencia em fase reversa (CLAE-FR) e os principais parâmetros farmacocineticos foram analisados atraves do emprego do software PKSolver (Ver 2.0). O ensaio de farmacocinetica clinica foi conduzido na clinica Pharmacological Center (No.JDX1999064) do Hospital de Xiangya, Central South University, China. Os parâmetros PK obtidos indicaram que a nova formulacao de capsulas de liberacao retardada e sustentada de cloridrato de diltiazem possue marcantes caracteristicas de liberacao retardada e controlada do farmaco.