OBJECTIVES: To investigate the role of a neural pathway from oxytocin (OXT) neurons in the paraventricular hypothalamic nucleus (PVN) to γ-aminobutyric acid (GABA) neurons (GABAergic neurons) in the trigeminal nucleus caudalis (TNC) in regulating pain sensitization in a mouse model of chronic migraine and to explore the underlying mechanisms. METHODS: A chronic migraine mouse model was established by intraperitoneal injection of nitroglycerin (NTG, 1 mg/mL, 10 mg/kg) on days 1, 3, 5, 7, and 9. The study consisted of four parts: PartⅠ: 24 male wild-type C57BL/6J mice were divided into four groups (n=6 in each), receiving single or repeated injection of NTG or saline, respectively. Immunofluorescence was used to detect c-Fos and OXT expression in the PVN. Part Ⅱ: 6 male OXT-Cre transgenic C57BL/6J mice were used for anterograde monosynaptic tracing combined with RNAscope and immunofluorescence to identify neural projections from PVN OXT neurons to TNC GABAergic neurons. Part Ⅲ: 30 male OXT-Cre transgenic C57BL/6J mice were bilaterally injected Cre-dependent chemogenetic activation virus into the PVN. These mice were randomly divided into five groups, with six mice in each group. Mice in the clozapine N-oxide (CNO) group and the control group were intra-peritoneally injected with 0.1 mg/mL of CNO solution (1 mg/kg) and the same volume of isotonic normal saline, respectively. 3 hours after the injection, the brain tissues were harvest and c-Fos immunofluorescence staining was performed to verify the efficiency of chemogenetic activation virus. Mice in the model control group and the CNO activated model group were subjected to chronic migraine modeling, with bilateral TNC injection of isotonic normal saline and CNO, respectively, on day 10. The mice in the negative control group were bilaterally intra-TNC injected with isotonic normal saline. After 30 minutes, the Von-Frey filament and acetone tests were used to assess the mechanical pain threshold and cold pain response time in the periorbital region of the mice in these three groups. Part Ⅳ: 24 male OXT-Cre transgenic C57BL/6J mice were bilaterally injected with the Cre-dependent chemogenetic activation virus into the PVN. These mice were randomly divided into four groups, with six mice in each group. Mice in the model control group, the CNO activated model group and the atosiban group were subjected to chronic migraine modeling. On day 10, mice in the negative control group and the model control group were intraperitoneally injected with isotonic normal saline, while mice in the CNO activated model group and the atosiban group were intraperitoneally injected with CNO. After 15 minutes, mice in the atosiban group were bilaterally intra-TNC injected with atosiban, while mice in other three groups were bilaterally intra-TNC injected with isotonic normal saline containing 1% dimethyl sulfoxide. After 15 minutes, the Von-Frey filament and acetone tests were used to assess the mechanical pain threshold and cold pain response time in the periorbital region of the mice. The GABA content in the bilateral TNC was detected by high-performance liquid chromatography (HPLC). RESULTS: Mice with chronic migraine models exhibited reduced periorbital mechanical pain thresholds and increased periorbital cold pain reaction time, accompanied by an increase in both the number of c-Fos⁺ neurons and the percentage of c-Fos⁺ OXT neurons in the PVN (all P<0.05). The anterograde tracing virus and RNAscope combined with immunofluorescence staining showed that PVN OXT neurons projected to TNC GABAergic neurons. Immuno-fluorescence staining demonstrated that compared with the control group, the percentage of c-Fos⁺ OXT neurons in the PVN of CNO group increased (P<0.05). In bilateral intra-TNC drug administration experiments, compared with the model control group, the periorbital mechanical pain threshold increased, and the periorbital cold pain reaction time decreased in the CNO activated model group (both P<0.05). In intraperitoneal drug administration experiments, compared with the CNO activate model group, the periorbital mechanical pain threshold decreased, and the periorbital cold pain reaction time increased in the atosiban group (both P<0.05). HPLC analysis showed that, compared with the negative control group, the model control group and the atosiban group, GABA level of TNC in the CNO activated model group increased (all P<0.05). CONCLUSIONS PVN OXT neurons exert a descending facilitatory effect on GABAergic neurons in the TNC via OXT release, thereby ameliorating pain sensitization in chronic migraine.
Animals ; Paraventricular Hypothalamic Nucleus/physiopathology* ; Male ; Mice, Inbred C57BL ; Migraine Disorders/physiopathology* ; Mice ; GABAergic Neurons/physiology* ; Oxytocin/physiology* ; Disease Models, Animal ; Neurons/physiology* ; Mice, Transgenic ; Neural Pathways ; Chronic Disease

Oxytocin is classically termed a 'prosocial neuropeptide' because of its evolutionarily conserved role in promoting affiliative behaviors. Endogenous oxytocin is mainly synthesized by hypothalamic oxytocin neurons and signals through oxytocin receptors (OxtRs). Recent studies with cell type-specific and circuit-specific interrogation have uncovered that oxytocin signals exert pleiotropic neuromodulatory effects through anatomically widespread axonal projections and ubiquitously distributed OxtRs. Dysfunctions of oxytocin signals are closely relevant to brain disorders/diseases. While intranasal oxytocin administration has been demonstrated to be one potential strategy to alleviate some brain disorders/diseases, such as autism, obesity, and anxiety, conflicting clinical outcomes highlight the imperative for precision-targeted neuromodulation strategies. Dissecting the molecular, cellular, and neural circuitry mechanisms underlying oxytocinergic modulation is a prerequisite to achieving this goal. This review provides an overview of the current understanding of the oxytocin system in terms of anatomical structure, neuronal modulation, and signal pathways, and discusses the modulatory roles of oxytocin in social, feeding, emotional, and sensory-related brain functions and brain diseases.
Oxytocin/metabolism* ; Humans ; Animals ; Hypothalamus/physiology* ; Brain/physiology* ; Brain Diseases/physiopathology* ; Receptors, Oxytocin/metabolism*

Magnetic stimulation has made significant strides in the treatment of psychiatric disorders. Nonetheless, current magnetic stimulation techniques lack the precision to accurately modulate specific nuclei and cannot realize deep brain magnetic stimulation. To address this, we utilized superparamagnetic iron oxide nanoparticles as mediators to achieve precise targeting and penetration. We investigated the effects of magnetic fields with varying frequencies on neuronal activity and compared the activation effects on neurons using a 10-Hz precise magneto-stimulation system (pMSS) with repetitive transcranial magnetic stimulation in mice. Oxytocin levels, dendritic morphology and density, and mouse behavior were measured before and after pMSS intervention. Our findings suggest that pMSS can activate oxytocinergic neurons, leading to upregulation of oxytocin secretion and neurite outgrowth. As a result, sociability was rapidly improved after a one-week pMSS treatment regimen. These results demonstrate a promising magneto-stimulation method for regulating neuronal activity in deep brain nuclei and provide a promising therapeutic approach for autism spectrum disorder.
Animals ; Autism Spectrum Disorder/physiopathology* ; Paraventricular Hypothalamic Nucleus/physiology* ; Disease Models, Animal ; Transcranial Magnetic Stimulation/methods* ; Male ; Social Behavior ; Mice ; Oxytocin/metabolism* ; Mice, Inbred C57BL ; Neurons/physiology*

The objective of this study was to investigate the effects of oxytocin infusion on corpus luteum (CL) function during early to mid-diestrus by measuring luteal size (LS) and luteal blood flow (LBF) along with plasma levels of progesterone (P4) and prostaglandin metabolites (13,14-dihydro-15-keto-prostaglandin F2alpha, PGFM). On day (D) 7 of the estrus cycle (D1 = ovulation), seven cows received 100 IU of oxytocin (OXY) or placebo (PL) following a Latin square design. LS and LBF increased in both groups over time and no differences were observed between the groups. PGFM did not differ either within the groups over time or between the groups at any time point. P4 of the OXY group was higher compared to that of the the PL group 360 min after the infusion (p = 0.01) and tended to be higher at the time points 450 min, 48 h, and 72 h (all p = 0.08). Results from this study support the hypothesis that OXY is not directly involved in the mechanism(s) governing blood flow of the CL and has no remarkable effects either on luteal size or P4 and PGFM plasma levels. Further investigation is needed to elucidate the role of OXY in CL blood flow during early and late luteal phases.
Animals ; Cattle/*physiology ; Corpus Luteum/blood supply/*drug effects/secretion/ultrasonography ; Dinoprost/analogs & derivatives/blood ; Estrous Cycle/*drug effects/physiology ; Female ; Immunoenzyme Techniques/veterinary ; Organ Size/physiology ; Oxytocin/*pharmacology ; Progesterone/blood/*secretion ; Random Allocation ; Ultrasonography, Doppler, Color/veterinary

Oxytocin (OT) is a female hormone with the main function of facilitating uterine contraction and milk ejection. Recent studies show that OT is involved in multiple signaling pathways in the central and peripheral nerve system and mainly regulates the physiology and activity of reproduction, including male reproduction and sexual behavior. The roles of OT in penile erection are bio-phasic with proerectile effect in the central nerve system while peripherally inhibiting erection. OT also mediates ejaculation, post-ejaculatory detumescence and the post-orgasm refractory period. OT and OT-receptor in the central nerve system will be a new target in the drug development for the treatment of erectile dysfunction, while OT intracavernous injection promises to be an effective therapy for priapism. This review focuses on the effects of OT on male sexual activities.
Humans ; Male ; Oxytocin ; physiology ; Penile Erection ; Sexual Behavior

OBJECTIVETo observe the effect of electroacupuncture (EA) of different acupoints on abnormal electrohysterogram (EHG) in pregnant rats, so as to analyze their regularities in regulating dysfunction of the viscera.

METHODSA total of 48 Wistar pregnant rats (18-20 days) anesthetized with mixture solution of 1.5% chloralose and 25% urethane (i. p) were randomized into control (n=10), "Sanyinjiao" (SP 6, n=9), "Hegu" (LI 4, n=8), "Neiguan" (PC 6, n=0), and "SP 6 + LI 4" (n=11) groups. EHG was recorded by using a bipolar stainless steel electrode inserted in the sub-perimetrium layer of the left mid part of the uterus. The reference electrode was placed beneath the skin of the incision. Oxytocin and gesterol were given to the local uterus nearby the recording electrode to induce abnormal excitement and suppression of EHG respectively. EA (1-2 mA, 2/15 Hz) was applied to the above-mentioned acupoints separately for 20 min in the EA groups and the influences of EA on the amplitude and frequency of burst (fast) waves and slow waves of EHG were analyzed.

RESULTSCompared with the control group, EA of SP 6 + LI 4 and SP 6 groups had apparent inhibitory effects on oxytocin-induced increases of the frequency and amplitude of both fast and slow waves (P<0.05); and EA of LI 4 also had a markedly inhibitory effect on the amplitude of fast waves (P<0.05). No marked effects on both frequency and amplitude of fast waves and slow waves of EHG were found in the PC 6 group (P>0.05). In comparison with the control group, EA of SP 6+LI 4 and SP 6 could relieve or significantly relieve progesterone-induced suppression of the frequency and amplitude of both fast and slow waves (P<0.05); and the effects of SP 6 + LI 4 appeared earlier and lasted longer than those of SP 6; while EA of LI 4 and PC 6 had no obvious effect on progesterone-induced changes of the frequency and amplitude of both fast and slow waves (P>0.05).

CONCLUSIONEA different acupoints have their own relative specificity in regulating abnormal EHG.

Acupuncture Points ; Animals ; Electroacupuncture ; Female ; Myometrium ; physiology ; Oxytocin ; pharmacology ; Pregnancy ; Pregnancy, Animal ; physiology ; Progesterone ; pharmacology ; Random Allocation ; Rats ; Rats, Wistar

OBJECTIVETo observe effects of Shujing Ketong soft capsules (SJKTSC) on activities of the uterine of the rat in vitro and in vivo.

METHODThe isolated rat uterine were mounted in the improved Genell solution with a final content of 0. 96, 1.92, 3.84 microg x g(-1) of SJKTSC at 37 degrees C; and 9. 6, 19. 2, 38.4 mg x kg(-1) of SJKTSC and 2 g x kg(-1) of Tongjingbao granules were given to the rat through the duodenum respectively. Their effects on frequency, amplitude and activity of contraction of rat uterus in vitro and in vivo were investigated.

RESULTSJKTSC could significantly inhibit the frequency, amplitude and activity of contraction of the normal rat uterus in vitro and decrease the oxytocin-induced increase of contraction of the rat uterus in vitro; lowered the frequency, amplitude and activity of the oxytocin-induced contraction of the rat uterus in vivo and inhibit the oxytocin-induced the strengthening of contraction of the rat uterus in vivo.

CONCLUSIONShujing Ketong soft capsules maybe used for treatment of dysmenorrhea induced by spasm of uterine smooth muscle.

Animals ; Capsules ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Dysmenorrhea ; drug therapy ; physiopathology ; Female ; In Vitro Techniques ; Muscle, Smooth ; drug effects ; physiology ; Oxytocin ; adverse effects ; Rats ; Rats, Wistar ; Time Factors ; Uterine Contraction ; drug effects ; Uterus ; drug effects ; physiology

OBJECTIVETo observe effects of Fufang Xiaojingtong capsules (FXJTC) on activities of the uterine smooth muscle of the rat in vitro and the uterus of the rabbit in vivo.

METHODThe isolated rat uterine smooth muscle strips were mounted in a Magnus bath containing Locke's solution with a final content of 12.48, 6.24 or 3.12 mg x mL(-1) of FXJTC at 37 degrees C; and 2.0, 1.0 and 0.5 g x kg(-1) of FXJTC and 2.0 g x kg(-1) of Tianqi Tongjing capsules were respectively given to the rabbits through the duodenum, respectively. Their effects on frequency, amplitude and activity of contraction of the rat uterus in vitro and the rabbit uterus in vivo were investigated.

RESULTFXJTC could significantly inhibit the frequency, amplitude and activity of contraction of the normal rat uterus in vitro and decrease the oxytocin-induced increase of contraction of the rabbit uterus in vitro; lowered the frequency, amplitude and activity of contraction of the rabbit uterus in vivo and inhibit the oxytocin-induced the strengthening of contraction of the rabbit uterus in vivo.

CONCLUSIONFufang Xiaojingtong capsules maybe used for treatment of dysmenorrhea induced by spasm of uterine smooth muscle.

Animals ; Capsules ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; pharmacology ; Female ; In Vitro Techniques ; Muscle Contraction ; drug effects ; Muscle, Smooth ; drug effects ; physiology ; Oxytocin ; antagonists & inhibitors ; Plants, Medicinal ; chemistry ; Rabbits ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Uterus ; drug effects ; physiology

This study was performed to determine the action mode of oxytocin antagonist. In Study 1, the duration of in vivo action of oxytocin antagonist I (AI) was examined. After infusing AI, oxytocin was given and repeated every hour for 5 hr. Uterine activities were monitored with a polygraph. Study 2 determined the effect of AI on uterine oxytocin receptor number (Rn) and binding affinity (Kd). AI treated rats were sacrificed at 0.5 and 4 hr later for receptor assay. In Study 1, the uterine contractile response to oxytocin was significantly inhibited (p>0.05) compared to controls at five min, 1 and 2 hr after injection of AI. No differences in response were detected compared to controls (p>0.05) at later hours. In Study 2, no differences (p>0.05) between the AI and control animals in either oxytocin receptor number or binding affinity was found. These data suggest that the major mode of AI action is via competitive inhibition at the uterine oxytocin receptor and not by altering receptor number or binding affinity. AI is suggested to have the potential of being a potent and specific tocolytic agent for prevention of preterm labor in human.
Animal ; Female ; Oxytocin/pharmacology ; Oxytocin/metabolism ; Oxytocin/antagonists & inhibitors* ; Rats ; Receptors, Oxytocin/metabolism ; Uterus/physiology ; Uterus/drug effects*

This study was performed to determine the action mode of oxytocin antagonist. In Study 1, the duration of in vivo action of oxytocin antagonist I (AI) was examined. After infusing AI, oxytocin was given and repeated every hour for 5 hr. Uterine activities were monitored with a polygraph. Study 2 determined the effect of AI on uterine oxytocin receptor number (Rn) and binding affinity (Kd). AI treated rats were sacrificed at 0.5 and 4 hr later for receptor assay. In Study 1, the uterine contractile response to oxytocin was significantly inhibited (p>0.05) compared to controls at five min, 1 and 2 hr after injection of AI. No differences in response were detected compared to controls (p>0.05) at later hours. In Study 2, no differences (p>0.05) between the AI and control animals in either oxytocin receptor number or binding affinity was found. These data suggest that the major mode of AI action is via competitive inhibition at the uterine oxytocin receptor and not by altering receptor number or binding affinity. AI is suggested to have the potential of being a potent and specific tocolytic agent for prevention of preterm labor in human.
Animal ; Female ; Oxytocin/pharmacology ; Oxytocin/metabolism ; Oxytocin/antagonists & inhibitors* ; Rats ; Receptors, Oxytocin/metabolism ; Uterus/physiology ; Uterus/drug effects*