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Behavioral testing was performed on days 10, 11, and 24 post-SNL surgery. Mechanical sensory thresholds were measured by hind paw withdrawal away from a series of von Frey filaments 0. The stimuli were consecutively introduced, regardless of direction ascending or descending.

If no withdrawal response was observed, then the next greater force was applied; when a response was detected, a lower force was used. Thermal nociceptive thresholds were evaluated 60 min after oral administration by determining the PWL upon application of a calibrated radiant heat source.

This stimulus was positioned under the center of the plantar surface of the right hind paw with the aid of an angled mirror. The PWL readings of five trials were averaged as the response latency. Extracellular recordings were conducted as previously described Ding et al. The physiological condition of the animals was monitored based on their blood pressure and rectal temperature, and was maintained within the indicated range.

The lumbar enlargement involving the spinal cord was isolated by laminectomy of vertebral segments L4 and L6, and the dural spinal segments were carefully removed. A small well was created at the monitored segment to allow for the application of vehicle or drugs.

Extracellular single-unit monitoring and WDR neuron identification were performed based on their responses to brush, von Frey filaments, and pinch stimulations. Motor performance was assessed 30 days after SNL using an automated accelerating Rota-rod apparatus Panlab Harvard Apparatus, Barcelona, Spain , at a velocity that gradually increased from 4 rpm to 40 rpm over a 5-min interval. Seven trials were performed Tan et al.

The latency that rats remained on the accelerating rod was recorded in seconds for all groups. Rats were given at least 2 h to acclimatize to the testing room prior to the experiment and the behaviors were conducted between am and pm. Tian et al. Chambers were cleaned using alcohol pad between animals. The sleeping states of the animals were observed for up to 30 min immediately after pentobarbital sodium injection. The number of mice that slept as evidenced by the disappearance of righting reflex for 1 min within 30 min was recorded.

The test was carried out between and Briefly, fresh tissues of the lumbar enlargement L3—L5 of the spinal cord were immediately collected, washed with deionized water, and then immersed in infiltration solutions. The sections on the slides were stained, rinsed in deionized water, dehydrated through an ethanol gradient, cleared in xylene, and coverslipped with Permount TM mounting medium. Tissue sections of the Golgi-stained coronal spinal cord were evaluated by light microscopy Nikon, Japan.

For spine analysis, specific criteria in screening dendritic segments were employed Crupi et al. Dendritic spines were identified based on specific morphological characteristics, and protrusions from dendritic branches with distinct necks were considered as spines Golden et al.

We resuspended the P2 in Membrane Protein Extraction Kit B, followed by vortexing 10 s and then laid on ice 5—10 min ; these steps were repeated twice. Then, the immunoblots were rinsed and allowed to hybridize with horseradish peroxidase-conjugated secondary antibodies of the same species source for 2 h at room temperature.

The expression of proteins was detected using an enhanced chemiluminescence kit Beyotime, Shanghai, China. Western blots were analyzed using ImageJ software. The data and statistical analysis comply with the recommendations on experimental design and analysis in pharmacology Curtis et al.

Figure 3. Spontaneous nociceptive behaviors due to noxious chemical stimuli were tested using the formalin test, which induced time-dependent biphasic responses. Figure 4. Effects of LPM on formalin-induced pain behaviors in mice. To further evaluate the analgesic effect of LPM, an SNL-induced neuropathic pain model in rats was established and all rats were tested for mechanical allodynia and thermal hyperalgesia. Figure 5. After SNL, the stimulus threshold for right-hind paw withdrawal was reduced in response to mechanical and thermal stimulus intensities.

These results indicated that LPM attenuated mechanical allodynia and thermal hyperalgesia in SNL rats, and the analgesic effect is similar to pregabalin. Representative extracellular recordings of the WDR neurons in response to spontaneous firing and mechanical stimulation brush, von Frey filaments, and pinch are shown in Figures 6A—D. Figure 6. A—D Representative extracellular recording raw traces of WDR neurons activity in response to spontaneous firing, brush, von Frey filaments and pinch 1 h after administration.

To test whether the dose of LPM used in the pain studies impaired the motoric behavior in rats, rota-rod test was performed on day 30 after SNL. The sham rats could remain on the rota-rod for up to Figure 7.

Rats were single administered with vehicle 0. One hour later, motor performance or locomotor activity were recorded. Pregabalin decreased the spontaneous locomotion of rats, and showed a trend to reduce rota-rod fall latency, which were not seen with LPM To test whether the dose of LPM used in the pain studies produced the sedative effect, we performed the locomotor activity test in normal rats. In the present study, pentobarbital sodium-induced sleeping test was used in normal mice to evaluate whether LPM had sleep-promoting effects.

In this study, we observed that LPM, unlike pregabalin, did not play a hypnotic role. Figure 8. Effect of LPM on sleeping onset treated by subthreshold dose of pentobarbital sodium in normal mice. A representative neuron and three dendritic segments were shown in Figures 9A—E. The density of mushroom spines increased Figure 9. Dendritic spines were examined in Golgi-stained coronal tissue sections of the spinal cord in SNL rats. A A representative WDR neuron of the dorsal horn.

B Magnified image of the neuron shown in A. C A dendritic segment from the sham group. D Approximately 31 days after SNL, a dendritic branch segment showed an increase in spine density. All dendritic spines from each group were assessed in terms of F total spine density G thin spine density, and H mushroom spine density. The SNL-vehicle group showed an increase in total spine density, thin spine density, and mushroom spines density compared to the sham animals, whereas these increase were reduced with LPM treatment.

To determine the underlying molecular mechanism of the effect of LPM on the enhanced synaptic transmission and subsequent pain modulation in the spinal cord after nerve injury, fresh spinal dorsal horns were prepared 31 days after SNL for Western blot analysis. Figure We also examined synapse-associated protein postsynaptic density protein PSD95 and synaptophysin.

Synaptic-vesicle associated synaptophysin was used as a presynaptic indicator of synaptogenesis. Only a slight and insignificant increase in synaptophysin level was observed after SNL surgery Figure 10J. To investigate the underlying molecular mechanism of LPM on synaptic structural plasticity, we analyzed the expression levels of endogenous phosphorylated Rac1 and RhoA, two members of small GTPase family.

Clinically used first-line drugs for the treatment of neuropathic pain e. It is well established that central monoaminergic system i. Signaling pathways involved in regulating neuropathic pain using LPM Other signaling cascades involving the Rho family of small GTPases Rac1, RhoA modulate spine morphology by remodeling the actin cytoskeleton. Formalin test is a commonly used persistent pain model that typically demonstrates two temporally different phases.

Here, we first examined the potential analgesic effect of LPM using formalin test in mice given the fact that this was a rapid and extensively validated assay for determining analgesic activity. We found that acute LPM treatment was efficacious in reducing the total time spent on flinching and licking the injected paw during phase II. This initial testing suggests that LPM may be able to enter the CNS and induce centrally mediated analgesic effects. The electrophysiological activity of spinal WDR neurons is a suitable in vivo model for pain assessment, including hyperexcitability Giordano, ; Baron et al.

To evaluate the potential sedative and somnolence effects of LPM, several behavioral tests were performed, including the locomotor activity, rota-rod test, and pentobarbital sodium-induced sleeping test. Combined, these findings demonstrate that the apparent analgesic effect of pregabalin in rats could be partly attributed to its sedation and somnolence effects, while LPM displays specific anti-nociceptive effect without producing sedation and somnolence.

Because, we observed marked analgesic effects of LPM in several animal pain measures, we subsequently examined the potential molecular mechanisms that may help explain the analgesic effects of LPM It is reported that neuropathic pain has been linked to dysfunction of the pain descending inhibitory pathways of the CNS. Descending modulatory system arising with incoming nociceptive signal from the cortex, hypothalamus amygdala and pretectal nucleus finally feeds down to the spinal dorsal horn to affect further inputs into the spinal cord, causing the feedback circuit to continue, in which 5-HT, NE, and DA are key monoamines involved in the modulation of pain descending inhibitory pathways Bannister et al.

Descending 5-HT pathway from the rostral ventromedial medulla, which has 5-HT-rich nucleus raphe magnus at its core, passes down neuronal signals to the dorsal horn, exerts pro- and anti-nociceptive actions on pain processing, in which the anti-nociceptive effects of brainstem 5-HT are largely mediated by spinal 5-HT 1A receptors Bannister et al. NE is sourced from brainstem nuclei A1—A7 , especially in locus ceruleus, A7 and A5 regions, that convey nociceptive signals to spinal loci in a similar manner as the descending 5-HT system.

Originating from the A11 region, descending DA pathway also plays an important role in the process of anti-nociception in multiple regions of the CNS, including the basal ganglia, thalamus, insular cortex, anterior cingulate cortex, periaqueductal gray, and spinal cord Taniguchi et al. The dorsal raphe nucleus provides the principal source of 5-HT innervation in the control of sleep—wake state.

The effect of 5-HT on sleep—wake behavior depends upon the degree to which the serotonergic system is activated, in which facilitatory effect in the regulation of wake is mainly via 5-HT 1A , 5-HT 1B receptors Monti, The available evidence suggested that during wake, there occurs an increase of burst firing activity of DA neurons, and an enhanced release of DA in the VTA, SNc, and a number of forebrain structures.

Results suggest that the potential analgesic mechanisms of LPM are due to the presynaptic reuptake inhibition of 5-HT, NE and DA in pain descending modulatory system, thereby increasing their concentrations in synaptic cleft and then inhibit post-synaptic neurotransmission including glutamate in the spinal dorsal horn.

However, LPM does not induce sedation and somnolence, which may be largely attributed to the presynaptic reuptake inhibition of DA, and partly 5-HT and NE reuptake inhibition in brain regions associated with sleep—wake cycle, considering that the NE and 5-HT reuptake inhibitor duloxetine produces significant sedation and somnolence. An important property of chronic pain regulation is synaptic plasticity. Synaptic plasticity, including functional plasticity and structural plasticity, may explain how the nervous system modifies its neuronal circuits to adapt, modify, and keep information.

These dynamic synaptic alterations are involved in the spinal dorsal horn during pain processing, in which synaptic functional plasticity reflects long-lasting potentiation of synaptic transmission. The activation of NMDAR and AMPAR is mediated by recruitment of additional receptors to the postsynaptic membrane and phosphorylation of existing synaptic receptors, in which NR2B and GluR1 have been suggested to play critical roles in regulating nociceptive pathways of the spinal dorsal horn Luo et al.

A plausible interpretation of LPMinduced analgesia may be that the increase in the release of presynaptic neurotransmitters i. The functional and structural plasticity of dendritic spines are regarded as visual indicators of synaptic plasticity and memory Nishiyama and Yasuda, Neuropathic pain induces dendritic spine remodeling, which occurs 28 days after spinal cord injury in dorsal horn neurons Kim et al. As such, we examined the dendritic spine remodeling by using Golgi-stained spinal cord dorsal horn neurons.

It was found that the remodeling of dendritic spines, as indicated by an increase in total spine density, thin and mushroom-shaped spine density, occurred after SNL and LPM treatment effectively reduced SNL-induced increase. Accumulating evidence has established that Rho GTPases, namely, RhoA and Rac1, can modulate actin polymerization and influence the morphology and function of spines Golden et al.

Activated Rac1 promotes dendritic spine growth and synaptic strength in dorsal horn neurons, whereas the RhoA-mediated signaling cascade promotes the polymerization of actin filaments, rearranges the cytoskeleton, and allows intracellular trafficking of various nociceptive signaling factors Ohsawa et al. Rac1 inhibitors, which inhibit Rac1 activity after spinal cord injury, reduce the expression of PSD95 Tan et al. The overexpression of PSD95 in the spinal dorsal horn can drive the maturation of excitatory glutamatergic synapses Sharma et al.

In conclusion, our present study provides the first line of evidence that LPM, a potential TRI, displays robust analgesic effects in rodent models of persistent pain and neuropathic pain without inducing sedation and somnolence, two sides effects commonly seen in clinical use of first-line analgesics for neuropathic pain such as pregabalin, duloxetine or gabapentin. Together, our findings strongly suggest that LPM is a promising treatment for neuropathic pain without inducing sedation and somnolence effects and warrants further investigation as a potential analgesic.

MY synthesized the compound. CL and JT designed the research work. NL and CL analyzed the data. NL drafted the manuscript. All authors read and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Bannister, K. Preclinical and early clinical investigations related to monoaminergic pain modulation.

Neurotherapeutics 6, — Baron, R. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. Berridge, C. Sleep Med. Bolden-Watson, C. Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci. Chaplan, S. Quantitative assessment of tactile allodynia in the rat paw. Methods 53, 55— Chen, T.

Simvastatin enhances activity and trafficking of alpha7 nicotinic acetylcholine receptor in hippocampal neurons through PKC and CaMKII signaling pathways. Crupi, R. Curtis, M. Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers. Ding, X. Feinberg, S. Google Scholar. Finnerup, N. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Giordano, J. The neurobiology of nociceptive and anti-nociceptive systems.

Pain Phys. Golden, S. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Iacono, L. Jarcho, J. The World Federation of Societies of Biological Psychiatry WFSBP provides guidelines about dosage, recommending a starting dose between 4—8 mg per day in older adults, and 8—12 mg per day at the standard dose. Nevertheless, Reboxetine has been effectively used for the treatment of different psychiatric disorders besides MD such as seasonal depression, ADHD, GAD, bulimia, hypoactive sexual disorder, and even schizophrenia [ 46 ].

With respect to seasonal affective disorder, a recent study comparing Escitalopram to Reboxetine found that response and remission rates were not significantly different in the two treatment groups. Time of onset, however, was shorter with Reboxetine, whereas Escitalopram showed less side effects [ 48 ]. Common side effects of Reboxetine are consistent with its anticholinergic properties and include dry mouth, constipation, headache, drowsiness, dizziness, excessive sweating, and insomnia [ 50 ].

Few data are available on safety in overdose. Atomoxetine is a selective NRI with only a slight affinity for other neurotransmitter transporters and receptors [ 52 ]. Atomoxetine acts on the presynaptic membrane by blocking the noradrenaline reuptake pump: in this way, the availability of intrasynaptic noradrenaline results increased [ 53 ]. Atomoxetine is not labeled as a stimulant and its main indication is the treatment of ADHD [ 54 ].

Atomoxetine is metabolized by the cytochrome P 2D6 and the clearance of other drugs metabolized by CYP enzymes is not influenced by Atomoxetine [ 55 ]. It has been investigated in the treatment of depression. However, the lack of a significant effect compared to placebo did not allow the molecule to be approved for the treatment of MD. In terms of tolerability, abdominal pain, loss of appetite, nausea, and vomiting are the most frequent side effects reported by patients with ADHD on Atomoxetine [ 58 ].

Even though not approved for mood disorders, the use of Atomoxetine in ADHD, a condition characterized by impaired executive functions, hyperactivity, inattentive and impulsive behaviors, may help to understand how the action on the noradrenergic system can affect cognitive and motor skills. SNRIs increase the levels of both serotonin and noradrenaline within the CNS by selectively inhibiting their reuptake in the synaptic clefts.

Venlafaxine and its active metabolite Desmetylvenlafaxine, Duloxetine, and Milnacipran are currently included in the class of the SNRIs. Venlafaxine blocks the synaptic reuptake of serotonin at lower doses, the noradrenaline reuptake at higher doses and the dopamine reuptake at the highest dosages [ 59 ].

Several randomized controlled trials demonstrated the efficacy and safety of Venlafaxine in the treatment of anxiety disorders including social anxiety disorder, GAD, posttraumatic stress disorder, panic disorder, and OCD [ 60 ]. Generally, Venlafaxine is well tolerated and its side effects usually decline with continued treatment [ 61 ]. Main reported side effects pertain the digestive e. Discontinuation rates are not higher than those reported with other antidepressant like Fluoxetine or Paroxetine [ 63 ].

For this reason, potential drug interactions may be higher for Venlafaxine than for Desvenlafaxine during concomitant administration with other medications that affect the CYP 2D6 pathway [ 65 ]. Main side effects include nausea, insomnia, decreased appetite, fatigue, somnolence, and constipation [ 68 ]. Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake. It has a low affinity for other receptors.

Duloxetine is currently approved for MD, peripheral diabetic neuropathic pain, female stress urinary incontinence, and GAD [ 70 ]. When Venlafaxine and Duloxetine were compared in the treatment of GAD, both resulted superior to placebo and equally effective [ 71 ]. Duloxetine is generally well tolerated and the most commonly observed side effects are nausea, dry mouth, headache, constipation, dizziness, and fatigue. Milnacipran is a SNRI with minor effects on any presynaptic or postsynaptic receptors [ 73 ].

With respect to its pharmacokinetic and pharmacodynamic profile, Milnacipran clearly differs from the other SNRIs. On the other hand, it is eliminated by renal excretion, therefore, particular attention should be paid to those patients with any renal failure. Milnacipran has been approved in some Asian countries for the treatment of MD and it is also effective in the treatment of fibromyalgia, fatigue, and anxiety symptoms.

The overall effectiveness and tolerability of Milnacipran versus other antidepressants do not seem to differ in the acute treatment of MD; both are superior to those of TCAs and comparable to those of SSRIs. In the treatment of MD, SNRIs may combine a shorter latency of onset with higher rates of overall remission compared to SSRIs, and may be of particular value in patients with comorbid somatic symptoms [ 60 ].

Several molecules share a relatively selective action on noradrenaline and dopamine transporters, enhancing their levels in the synaptic cleft, such as Amineptine, Methylphenidate, Pipradol, and Nomifensine [ 74 ]. However, many of these compounds have shown major side effects due to their structure and action, which are actually similar to psychostimulant drugs.

Even two phytochemical compounds, derived from St. John's Wort Hypericum perforatum —Hyperforin and Adhyperforin—were found to positively act on a transient receptor potential ion channel causing an inhibition of monoamine reuptake while interfering with the entry of sodium and calcium into the cell [ 75 ]. The most widely used compound in this class is represented by Bupropion. They both act on monoamines reuptake, amphetamines by enhancing their release, Bupropion by blocking not permanently their reuptake.

Bupropion acts as a quite selective dopamine reuptake inhibitor [ 76 , 77 , 78 ], anyway its affinity in vitro is weaker than many drugs or even some SSRIs, such as Sertraline. Despite the lack of affinity, Bupropion increases the expression of dopamine transporter mRNA, rising dopamine concentration [ 79 , 80 , 81 ]. This increase of noradrenaline further inactivates dopamine [ 82 ]. Finally, Bupropion works indirectly on serotonin metabolism and possibly inhibits alpha3beta4 nicotinic receptors [ 83 ].

Hydroxybupropion is its main metabolite Radafaxine , but it also has many other metabolites eliminated through renal excretion. Maximum concentration is reached in 2—3 h and the steady state in 5—8 days. Therapeutic indications are broadly MD with melancholic features and seasonal depression, but its first use was for smoking cessation with reduced urge of smoking rate [ 83 ].

Further proposed treatment perspectives include the management of sexual dysfunction induced by serotonergic antidepressants, chemotherapy, and even those of primary origin as well as ADHD [ 84 , 85 , 86 ]. However, this result is controversial as a higher rate of remission than Venlafaxine has been reported as well [ 89 ]. Bupropion has been also used in augmentation to SSRIs, showing a favorable profile of tolerability [ 90 ]. Bupropion is not indicated for patients with a clinical history of seizure and, as all antidepressants, should be used with caution in bipolar depression due to the risk of mania induction.

Seizure was the main adverse effect that provoked the revocation from the market for most NDRIs. Nonetheless, this potential risk needs to be taken into account when the compound is prescribed in patients with brain tumors, substance or alcohol discontinuation, and with anorexia or bulimia nervosa. Concerning metabolism, patients with liver or kidney failure should receive a lower dosage of Bupropion.

Most commonly reported side effects include nausea, insomnia, sweating, and anxiety. Hypertension without effect on heart frequency rate has been reported as well [ 92 ]. Some of its metabolites are supposed to play a role both in therapeutic and toxic effects [ 94 ]. Mianserin was originally designed as an antiallergic drug. It has sedative properties and the most frequently reported side effect is drowsiness, which often diminishes within the first week of treatment.

As observed in clinical trials, peripheral anticholinergic effects are less frequent than with tricyclics. Of note, the lack of cardiovascular side effects such as increased heart rate and hypotension is a further important advantage of Mianserin [ 95 , 96 ]. Mianserin is indicated for the treatment of depression associated with anxiety and agitation and, like Mirtazapine, it is particularly indicated for patients experimenting insomnia [ 97 ].

The blockade of presynaptic autoreceptors ultimately enhances the noradrenaline release. On the other hand, the blockade of heteroreceptors on serotonergic neurons increases serotonin release. Unlike Venlafaxine, Mirtazapine has minimum effects on monoamine reuptake. Along with Amineptine, Bupropion, and Moclobemide, Mirtazapine is one of the antidepressants with the lowest risk of sexual dysfunction [ 98 , 99 ].

Mirtazapine may be particularly suitable for selected subgroups of patients like severely depressed ones, especially those at midlife and older. Its side effect profile is still somewhat more favorable than that of tricyclics [ ]. Mirtazapine has also shown some degree of effectiveness in the treatment of anxiety disorders including posttraumatic stress disorder, panic disorder, social anxiety disorder, and OCD and undifferentiated somatoform disorder [ ].

Each of these compounds is characterized by a peculiar affinity for the different transporters [ ]. Each of these molecules has active metabolites which, in turn, may have antidepressant effects. A faster onset of action is a main expectation for TRIs [ ]. Ultimately, the major aim of TRIs would be to achieve greater efficacy in terms of response and remission rates while maintaining a favorable profile of tolerability due to the selective action on the monoamine transporters.

At present time no TRI is in the market, while most of them are undergoing preclinical trials. Quetiapine, an atypical antipsychotic traditionally used for the treatment of Schizophrenia, has been successfully used over the last years in the treatment of depression, bipolar depression in particular [ ]. Converging evidence that compounds acting on the noradrenergic neurotransmission are more effective than those with pure serotonergic action exists.

Compared to tricyclics, response to Venlafaxine was estimated to be greater but not to a statistically significant extent. No difference in remission rates was observed. These data might suggest that antidepressants with a noradrenergic action are more effective in the treatment of severe depression than those with an exclusive serotonergic component. Besides, in the cited study, those antidepressants with a greater degree of noradrenergic inhibition or dual action i.

The superior efficacy of these antidepressants may be related to their noradrenergic component [ ]. On the other hand, different studies indicate that SSRIs i. It would be of great clinical interest not only to compare the efficacy and tolerability of noradrenergic and mixed antidepressants among themselves and in comparison to the SSRIs in affective disorders, but also to assess how the noradrenergic action translates in terms of symptom improvement.

For instance, when this was done in previous studies [ 13 ], important correlations emerged in terms of specific antidepressant action and initial symptom improvement e. Further studies in this perspective would be therefore highly appreciated in order to rationally develop new drugs and better understand the effect of the current ones.

In conclusion, despite the striking advances in the pathophisiology of affective disorders of the last decade, the noradrenergic system still has a pivotal role in the clinical psychopharmacology of antidepressants. Pharmacogenomic and pharmacogenetic studies in the next future should help clinicians to understand which patients are supposed to better respond to a specific antidepressant rather than to another one.

National Center for Biotechnology Information , U. CNS Neurosci Ther. Published online Dec Carlotta Palazzo , 1 Lucio Oldani , 1 and A. Carlo Altamura 1. Carlotta Palazzo. Carlo Altamura. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC.

SUMMARY Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression MD , noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors SSRIs.

Keywords: Major depression, Noradrenaline, Noradrenergic compounds. Introduction It is well established that many antidepressant compounds with proven clinical efficacy act also on noradrenergic pathways. Neuroanatomy of Noradrenergic Transmission The main noradrenergic brain circuits are located in the locus coeruleus, which consists of a major group of noradrenergic neurons in the periventricular and periaqueductal gray matter, connecting the cerebral cortex, the cerebellum, and the brainstem.

Biochemistry Noradrenaline is a cathecholamine with a hormonal role increasing the glycogenolysis, heart rate, and blood flow: these actions result on a global arousal state in the stress response. Behavioral Correlates of Noradrenergic Systems As previously mentioned, noradrenergic transmission seems to be particularly correlated with attention, arousal, motor, and cognitive activity [ 15 , 17 ]. Table 1 Dose range, clinical indications, and main side effects of psychotropic compounds with noradrenergic action.

Open in a separate window. Table 2 Affinity for noradrenalin transporter NET for some pronoradrenergic compounds. Aim of the Study The present article is aimed to provide a comprehensive and updated overview in relation to the noradrenergic action of currently available antidepressants, focusing on main pharmacological mechanisms of action, pharmacodynamic and pharmacokinetic properties, and clinical indications.

Material and Methods Articles for inclusion were identified conducting a literature search in PubMed referring, in particular, to the last 10 years from January to June Results More than articles were identified and the following classes of antidepressants and related compounds were carefully examined: tricyclics with prominent noradrenergic activity i.

Monoamine Oxidase Inhibitors The monoamine oxidase inhibitors MAOIs act by inhibiting the activity of the enzyme monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and increasing their available stores. Noradrenenaline Reuptake Inhibitors Reboxetine Reboxetine acts binding the NAT and blocking the reuptake of extracellular noradrenaline into terminals, with low affinity for other transporters or receptors [ 42 ]. Atomoxetine Atomoxetine is a selective NRI with only a slight affinity for other neurotransmitter transporters and receptors [ 52 ].

Serotonin Noradrenaline Reuptake Inhibitors SNRIs increase the levels of both serotonin and noradrenaline within the CNS by selectively inhibiting their reuptake in the synaptic clefts. Venlafaxine and Desmetylvenlafaxine Venlafaxine blocks the synaptic reuptake of serotonin at lower doses, the noradrenaline reuptake at higher doses and the dopamine reuptake at the highest dosages [ 59 ].

Duloxetine Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake. Milnacipran Milnacipran is a SNRI with minor effects on any presynaptic or postsynaptic receptors [ 73 ]. Noradrenaline Dopamine Reuptake Inhibitor Several molecules share a relatively selective action on noradrenaline and dopamine transporters, enhancing their levels in the synaptic cleft, such as Amineptine, Methylphenidate, Pipradol, and Nomifensine [ 74 ].

Atypical Antipsychotics Quetiapine Quetiapine, an atypical antipsychotic traditionally used for the treatment of Schizophrenia, has been successfully used over the last years in the treatment of depression, bipolar depression in particular [ ]. Discussion Converging evidence that compounds acting on the noradrenergic neurotransmission are more effective than those with pure serotonergic action exists.

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About half were prescribed fluvoxamine and half were given a placebo. By May we had spent the money and I was unsure what to do; we only had about 60 recruited. He has a history of giving away some of his millions to good causes, and when COVID began killing people last year, he had no intention of watching the destruction from the sidelines. He made sure the bodies of the Muslim dead faced Mecca. COVID claimed his life. Kirsch, who earned his fortune by starting Infoseek and several other companies, consulted with scientists about where his money might do the most good and came up with a plan: funding research into existing drugs that might be effective against the virus.

Then he recruited a member board of medical experts to review grant applications from researchers. Fifty proposals sailed in, and Kirsch was particularly skeptical of one of them. The one submitted by Lenze and Reiersen. The pandemic, in all its deadly fury, has unleashed a global response, with the best minds in far-flung places responding to the call for innovative remedies. Much of the attention has been focused on the large corporations and research groups racing to develop vaccines, often with government support and encouragement.

But individual doctors, scientists and philanthropists like Kirsch have also stepped up to supplement and inform government action. Kirsch himself called Lenze with the news. Lenze called with highly encouraging results. The trial had been small, but none of the patients treated with fluvoxamine deteriorated, while six of those receiving the placebo did.

If it had been up to Kirsch, fluvoxamine would have immediately become a go-to therapeutic tool on the basis of that trial. But others, including Reiersen and Lenze, felt more research was necessary, despite the strongly encouraging results. Carefully conducted, exhaustive large-scale trials exist for a reason. Taking a shortcut, in this case with a mind-altering drug produced for an entirely different purpose than treating COVID, can carry unintended or unforeseen risks.

Living in space can get lonely. What helps? Talking to random people over ham radio. From their living rooms and pickup trucks, amateur radio operators reach out to the International Space Station, circling miles above Earth. Some studies, for example, suggested that hydroxychloroquine might be useful in treating COVID, and it was widely touted by President Trump and others.

At the same time that Lenze and Reiersen were beginning their look at fluvoxamine, a psychiatrist in France had noticed something he found remarkable. As the virus raged through every sector of French society, psychiatric patients were not getting sick at the same rate or with symptoms that were as severe. Nicolas Hoertel, associate professor of psychiatry at Paris University and a psychiatrist at a hospital just outside the city. Could it be, he wondered, that the patients were getting some protection from their prescribed antidepressants?

Hoertel said he checked with colleagues at hospitals in and around Paris and found others who had made the same observation. Reiersen and Lenze had no idea that doctors in France were sniffing up the same trail. Kirsch was ever more determined to spread the word, and got a chance to do so on Nov.

His host was Dr. David Seftel, chief executive of a Bay Area disease diagnosis company called Enable Biosciences and longtime physician at Golden Gate Fields, the horse racetrack in Berkeley. He suspected the virus spread quickly because so many of the employees live at the track, in close proximity, while caring for the horses.

The virus hit all age groups, with a range of severity. Based on the study by Lenze and Reiersen, he decided to offer fluvoxamine to sick employees who wanted to try it. Seftel said a couple of his patients reported mild nausea and abdominal discomfort, but those disappeared after he slightly altered the dosage.

The antidepressant can interact with other drugs a patient is taking and can have side effects, including abdominal discomfort and sleep disturbances. In St. Louis, Lenze and Reiersen are hustling to complete that larger study. They have recruited symptomatic participants from Los Angeles and elsewhere, with a goal of patients. Anyone interested in learning more or signing up for the trial can do so at stopcovidtrial. There are 19 million new cases of sexually transmitted infections every year in the U.

Of the 2. The World Health Organization also stated that the "estimated 1. In cases where infection is suspected, early medical intervention is highly beneficial in all cases. They added that "several co-factors may increase the risk of HIV transmission through oral sex"; this includes ulcers, bleeding gums , genital sores, and the presence of other STIs.

In , the World Health Organization estimated that million women become pregnant worldwide each year, and around 87 million of those pregnancies or Approximately 46 million pregnancies per year reportedly end in induced abortion. However, many more women become pregnant and miscarry without even realizing it, instead mistaking the miscarriage for an unusually heavy menstruation.

This data includes live births, abortions, and fetal losses. It has been linked to atypical levels of dopamine, a neurotransmitter. This behavior is characterized by a fixation on sexual intercourse and disinhibition. It was proposed that this 'addictive behavior' be classified in DSM-5 as an impulsive—compulsive behavioral disorder.

Addiction to sexual intercourse is thought to be genetically linked. Those having an addiction to sexual intercourse have a higher response to visual sexual cues in the brain. Those seeking treatment will typically see a physician for pharmacological management and therapy. It is manifested by hypersomnia and hypersexuality and remains relatively rare. Sexual activity can directly cause death , particularly due to coronary circulation complications, which is sometimes called coital death, coital sudden death or coital coronary.

Sexual intercourse, when involving a male participant, often ends when the male has ejaculated, and thus the partner might not have time to reach orgasm. In , scholars from the Kinsey Institute stated, "The truth is that the time between penetration and ejaculation varies not only from man to man, but from one time to the next for the same man.

But he didn't ask if the men or their partners considered two minutes mutually satisfying" and "more recent research reports slightly longer times for intercourse". Anorgasmia is regular difficulty reaching orgasm after ample sexual stimulation, causing personal distress. Vaginismus is involuntary tensing of the pelvic floor musculature, making coitus, or any form of penetration of the vagina, distressing, painful and sometimes impossible for women.

It is a conditioned reflex of the pubococcygeus muscle, and is sometimes referred to as the PC muscle. Vaginismus can be hard to overcome because if a woman expects to experience pain during sexual intercourse, this can cause a muscle spasm, which results in painful sexual intercourse. For those whose impotence is caused by medical conditions, prescription drugs such as Viagra , Cialis , and Levitra are available.

However, doctors caution against the unnecessary use of these drugs because they are accompanied by serious risks such as increased chance of heart attack. Sexual intercourse remains possible after major medical treatment of the reproductive organs and structures. This is especially true for women. Even after extensive gynecological surgical procedures such as hysterectomy , oophorectomy , salpingectomy , dilation and curettage , hymenotomy , Bartholin gland surgery, abscess removal, vestibulectomy , labia minora reduction, cervical conization , surgical and radiological cancer treatments and chemotherapy , coitus can continue.

Reconstructive surgery remains an option for women who have experienced benign and malignant conditions. Obstacles that those with disabilities face with regard to engaging in sexual intercourse include pain, depression , fatigue, negative body image , stiffness, functional impairment, anxiety, reduced libido , hormonal imbalance, and drug treatment or side effects.

Sexual functioning has been regularly identified as a neglected area of the quality of life in patients with rheumatoid arthritis. The mentally disabled also are subject to challenges in participating in sexual intercourse. Women with Intellectual disabilities ID are often presented with situations that prevent sexual intercourse. This can include the lack of a knowledgeable healthcare provider trained and experienced in counseling those with ID on sexual intercourse. Those with ID may have hesitations regarding the discussion of the topic of sex, a lack of sexual knowledge and limited opportunities for sex education.

In addition there are other barriers such as a higher prevalence of sexual abuse and assault. These crimes often remain underreported. There remains a lack of "dialogue around this population's human right to consensual sexual expression, undertreatment of menstrual disorders, and legal and systemic barriers". Women with ID may lack sexual health care and sex education. They may not recognize sexual abuse. Consensual sexual intercourse is not always an option for some. Those with ID may have limited knowledge and access to contraception, screening for sexually transmitted infections and cervical cancer.

Sexual intercourse may be for reproductive, relational, or recreational purposes. In humans and bonobos , the female undergoes relatively concealed ovulation so that male and female partners commonly do not know whether she is fertile at any given moment. One possible reason for this distinct biological feature may be formation of strong emotional bonds between sexual partners important for social interactions and, in the case of humans, long-term partnership rather than immediate sexual reproduction.

Sexual dissatisfaction due to the lack of sexual intercourse is associated with increased risk of divorce and relationship dissolution, especially for men. For women, there is often a complaint about the lack of their spouses' sexual spontaneity. Decreased sexual activity among these women may be the result of their perceived failure to maintain ideal physical attractiveness or because their sexual partners' health issues have hindered sexual intercourse. Research additionally indicates that non-married couples who are cohabiting engage in sexual intercourse more often than married couples, and are more likely to participate in sexual activity outside of their sexual relationships; this may be due to the " honeymoon " effect the newness or novelty of sexual intercourse with the partner , since sexual intercourse is usually practiced less the longer a couple is married, with couples engaging in sexual intercourse or other sexual activity once or twice a week, or approximately six to seven times a month.

Adolescents commonly use sexual intercourse for relational and recreational purposes, which may negatively or positively impact their lives. For example, while teenage pregnancy may be welcomed in some cultures, it is also commonly disparaged, and research suggests that the earlier onset of puberty for children puts pressure on children and teenagers to act like adults before they are emotionally or cognitively ready.

Some studies from the s through s suggested an association between self-esteem and sexual intercourse among adolescents, [] while other studies, from the s and s, reported that the research generally indicates little or no relationship between self-esteem and sexual activity among adolescents. Psychiatrist Lynn Ponton wrote, "All adolescents have sex lives, whether they are sexually active with others, with themselves, or seemingly not at all", and that viewing adolescent sexuality as a potentially positive experience, rather than as something inherently dangerous, may help young people develop healthier patterns and make more positive choices regarding sexual activity.

High-quality romantic relationships are associated with higher commitment in early adulthood, [] and are positively associated with social competence. While sexual intercourse, as coitus, is the natural mode of reproduction for the human species, humans have intricate moral and ethical guidelines which regulate the practice of sexual intercourse and vary according to religious and governmental laws.

Some governments and religions also have strict designations of "appropriate" and "inappropriate" sexual behavior, which include restrictions on the types of sex acts which are permissible. A historically prohibited or regulated sex act is anal sex. Sexual intercourse with a person against their will, or without their consent , is rape , but may also be called sexual assault ; it is considered a serious crime in most countries.

Most countries have age of consent laws which set the minimum legal age with whom an older person may engage in sexual intercourse, usually set at 16 to 18, but ranges from 12 to 20, years of age. In some societies, an age of consent is set by non-statutory custom or tradition.

Some countries treat any sex with a person of diminished or insufficient mental capacity to give consent, regardless of age, as rape. Robert Francoeur et al. Kalbfleisch and Michael J. Over time, the meaning of rape broadened in some parts of the world to include many types of sexual penetration, including anal intercourse, fellatio, cunnilingus, and penetration of the genitals or rectum by an inanimate object. In , they changed the meaning from "The carnal knowledge of a female forcibly and against her will" to "The penetration, no matter how slight, of the vagina or anus with any body part or object, or oral penetration by a sex organ of another person, without the consent of the victim.

In most societies around the world, the concept of incest exists and is criminalized. James Roffee, a senior lecturer in criminology at Monash University , [] addressed potential harm associated with familial sexual activity, such as resulting children born with deficiencies. However, the law is more concerned with protecting the rights of people who are potentially subjected to such abuse.

This is why familial sexual relationships are criminalized, even if all parties are consensual. There are laws prohibiting all kinds of sexual activity between relatives, not necessarily penetrative sex. These laws refer to grandparents, parents, children, siblings, aunts and uncles. There are differences between states in terms of the severity of punishments and what they consider to be a relative, including biological parents, step-parents, adoptive parents and half-siblings.

Another sexual matter concerning consent is zoophilia , which is a paraphilia involving sexual activity between human and non-human animals, or a fixation on such practice. Sexual intercourse has traditionally been considered an essential part of a marriage, with many religious customs requiring consummation of the marriage and citing marriage as the most appropriate union for sexual reproduction procreation.

Sexual relations between marriage partners have been a "marital right" in various societies and religions, both historically and in modern times, especially with regard to a husband's rights to his wife. Adultery engaging in sexual intercourse with someone other than one's spouse has been, and remains, a criminal offense in some jurisdictions. With regard to divorce laws , the refusal to engage in sexual intercourse with one's spouse may give rise to a grounds for divorce , which may be listed under "grounds of abandonment".

Dwyer stated that no-fault divorce laws "have made it much easier for a woman to exit a marital relationship, and wives have obtained greater control over their bodies while in a marriage" because of legislative and judicial changes regarding the concept of a marital exemption when a man rapes his wife.

There are various legal positions regarding the meaning and legality of sexual intercourse between persons of the same sex or gender. Blanchflower , it was held that female same-sex sexual relations, and same-sex sexual practices in general, did not constitute sexual intercourse, based on a entry in Webster's Third New International Dictionary that categorizes sexual intercourse as coitus; and thereby an accused wife in a divorce case was found not guilty of adultery.

Opposition to same-sex marriage is largely based on the belief that sexual intercourse and sexual orientation should be of a heterosexual nature. A related issue is whether the word marriage should be applied. There are wide differences in religious views with regard to sexual intercourse in or outside of marriage:. In some cases, the sexual intercourse between two people is seen as counter to religious law or doctrine.

In many religious communities, including the Catholic Church and Mahayana Buddhists , religious leaders are expected to refrain from sexual intercourse in order to devote their full attention, energy, and loyalty to their religious duties. In zoology , copulation often means the process in which a male introduces sperm into the female's body, especially directly into her reproductive tract. Before mating and copulation, the male spider spins a small web and ejaculates on to it.

He then stores the sperm in reservoirs on his large pedipalps , from which he transfers sperm to the female's genitals. The females can store sperm indefinitely. Many animals that live in water use external fertilization , whereas internal fertilization may have developed from a need to maintain gametes in a liquid medium in the Late Ordovician epoch. Internal fertilization with many vertebrates such as reptiles , some fish , and most birds occur via cloacal copulation see also hemipenis , while mammals copulate vaginally, and many basal vertebrates reproduce sexually with external fertilization.

For primitive insects , the male deposits spermatozoa on the substrate, sometimes stored within a special structure; courtship involves inducing the female to take up the sperm package into her genital opening, but there is no actual copulation. In dragonflies, it is a set of modified sternites on the second abdominal segment. Bonobos, chimpanzees and dolphins are species known to engage in heterosexual behaviors even when the female is not in estrus, which is a point in her reproductive cycle suitable for successful impregnation.

These species are also known to engage in same-sex sexual behaviors. From Wikipedia, the free encyclopedia. Redirected from Penis in vagina. This article is primarily about humans. For other animals, see Animal sexual behaviour. For other uses, see Sex disambiguation. For copulation among other animals, see Copulation zoology.

Copulation for reproduction or sexual pleasure, or other penetrative sex acts for sexual pleasure. See also: Human sexual activity and Human sexuality. Main articles: Sexual reproduction and Human reproduction. See also: Coitus interruptus. See also: Intravaginal ejaculation latency time and Coitus reservatus. Main article: Sexuality and disability.

See also: Human mating strategies and Pair bond. Main article: Adolescent sexuality. See also: Sexual ethics , Religion and sexuality , and Sex and the law. See also: Religion and sexuality. Main articles: Copulation zoology and Animal sexual behaviour. See also: Sexual coercion. Human sexuality portal. See, for example; "Sexual intercourse". Retrieved November 22, Retrieved December 5, Retrieved May 9, Richard M.

Lerner ; Laurence Steinberg Handbook of Adolescent Psychology. Retrieved April 29, Encyclopedia of Sex and Gender: A-C. Macmillan Reference. Sexual intercourse. This 'coming together' is generally understood in heteronormative terms as the penetration of a woman's vagina by a man's penis. Irving B. Weiner; W. Edward Craighead The Corsini Encyclopedia of Psychology. Retrieved August 21, Human sexual intercourse, or coitus, is one of the most common sexual outlets among adults.

Sexual intercourse generally refers to penile penetration of the vagina. Clint E. Bruess; Elizabeth Schroeder Sexuality Education Theory and Practice. In many cultures around the world, vaginal sex is what is usually implied when people refer to 'having sex' or 'sexual intercourse. Cecie Starr; Beverly McMillan Human Biology. Cengage Learning.

Retrieved December 27, Coitus and copulation are both technical terms for sexual intercourse. The male sex act involves an erection, in which the limp penis stiffens and lengthens. It also involves ejaculation, the forceful expulsion of semen into the urethra and out from the penis. The stimulation triggers rhythmic, involuntary contractions in smooth muscle in the male reproductive tract, especially the vas deferens and the prostate.

The contractions rapidly force sperm out of each epididymis. They also force the contents of seminal vesicles and the prostate gland into the urethra. The resulting mixture, semen, is ejaculated into the vagina. Janell L. Carroll Sexuality Now: Embracing Diversity.

Vaginal intercourse also referred to as sexual intercourse involves inserting the penis into the vagina. Essential Concepts for Healthy Living. Most heterosexuals are familiar with the notion of 'having sex' or sexual intercourse as vaginal sex, the insertion of a penis into a vagina. Vaginal sex, or coitus, is the most common and popular form of intimate sexual activity between partners. Archived from the original on August 22, Retrieved January 12, Human Sexuality in a World of Diversity.

Discovering Biological Psychology. World Health Organization. January Retrieved September 5, In English, the term 'sex' is often used to mean 'sexual activity' and can cover a range of behaviours. Other languages and cultures use different terms, with slightly different meanings.

Nancy W. Denney; David Quadagno Human Sexuality. Mosby-Year Book. Although the term intercourse is usually used to refer to the insertion of the penis into the vagina, it is also used to refer to oral intercourse or anal intercourse in which the penis is inserted into the mouth or the anus, respectively. Dianne Hales The Encyclopedia of Mental Health. Infobase Publishing. An Invitation to Health Brief — Sexually Transmitted Infections. Elsevier Health Sciences.

Carpenter LM NYU Press. Retrieved October 8, Most people agree that we maintain virginity as long as we refrain from sexual vaginal intercourse. But occasionally we hear people speak of 'technical virginity' [ Advanced biology. Oxford University Press. Retrieved October 21, Pearson Education India. Petri, John M. Govern Motivation: Theory, Research, and Application. Trends Ecol. Palgrave Macmillan. Fedwa Malti-Douglas Ada P. Kahn; Jan Fawcett Carroll JL Health and Wellness for Life.

Human Kinetics. Retrieved September 6, Retrieved August 23, Retrieved August 24, The widespread, unquestioned equation of penile—vaginal intercourse with sex reflects a failure to examine systematically 'whether the respondent's understanding of the question matches what the researcher had in mind.

Laura M. Carpenter In many cultures around the world, vaginal sex is what is usually implied when people refer to 'having sex' or 'sexual intercourse'. It is the most frequently studied behavior and is often the focus of sexuality education programming for youth. Retrieved March 30, Retrieved December 26, Concise Medical Dictionary. Retrieved July 4, Journal of Pediatric and Adolescent Gynecology.

Harvey B. Milkman; Kenneth W. Wanberg Retrieved October 9, Cohen But occasionally we hear people speak of 'technical virginity' Data indicate that 'a very significant proportion of teens ha[ve] had experience with oral sex, even if they haven't had sexual intercourse, and may think of themselves as virgins'.

Robert Crooks; Karla Baur Our Sexuality. Noncoital forms of sexual intimacy, which have been called outercourse, can be a viable form of birth control. Outercourse includes all avenues of sexual intimacy other than penile—vaginal intercourse, including kissing, touching, mutual masturbation, and oral and anal sex. UD, TK Like a Virgin. The Advocate. Here Publishing. Retrieved March 13, Retrieved February 12, Exploring the Dimensions of Human Sexuality.

McAnulty; M. Michele Burnette Andrew Baum; Tracey A. Revenson; Jerome Singer Psychology Press. Having started with a discussion of penile-vaginal intercourse as the act that designates sexual initiation, as defined in most studies, we would like to undercut that position by stressing the need to define sex more broadly.

Retrieved April 30, Gender Power and Communication in Human Relationships. June Archived from the original PDF on May 10, Retrieved August 30, The Epidemic: A History of Aids. Many men simply did not like the feel of condoms, or associated them with emasculation. They say, 'Unless it's flesh on flesh, it's not real sex Wekwete African Books Collective.

Lloyd; Dana S. Dunn; Elizabeth Yost Hammer Retrieved January 5, The man-above, or "missionary," position is the most common [sex position]. The Big Book of Sex Toys. Retrieved June 9, Essential Concepts for Healthy Living Update. Retrieved December 9, Knobil and Neill's Physiology of Reproduction. Reis; Susan Sprecher; Susan K. Sprecher Encyclopedia of Human Relationships. Oxford University Press, 2nd edition. Neurobiology of Chemical Communication.

Lotus Press. Retrieved August 17, Janicak A Lange clinical manual. Clinical Psychology Review. Obstetrics and Gynecology Clinics of North America. Most women report the inability to achieve orgasm with vaginal intercourse and require direct clitoral stimulation The case of the female orgasm: bias in the science of evolution. Harvard University Press. The Journal of Urology. The Orgasm Answer Guide. JHU Press. Retrieved November 6, New York University Press. Retrieved March 2, Retrieved June 23, Human Reproduction.

Human Reproductive Biology. Academic Press. Retrieved November 8, New York: HarperCollins. Mayo Clinic. November 2, Retrieved February 16, National Institute for Health and Care Excellence. Published date: February Philip B. American Pregnancy Association. The Handy Anatomy Answer Book.

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This process of vesicle trafficking neoplastic cells at the migrating. Texas consensus conference panel on inhibitor treatment for major depressive. Those bettinger lopez ssrni motivated us to characterize the function of ERICH3 in order to help us. Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Retrieved November 6, New York. Predictors of remission in depression to individual and combined treatments PReDICT : study protocol for understand its role in antidepressant. Cell culture media was also January 5, The man-above, or a nationally representative sample of. Bipolar disorder in the elderly. Retrieved October 21, Pearson Education. The genotype-tissue expression GTEx project.

J. J. Bettinger PharmD Levomilnacipran is the levo‐enantiomer of milnacipran and is the only SNRI that is more potent for inhibiting NE. TCA, tricyclic antidepressant; SNRI, serotonin noradrenaline reuptake inhibitor; Seguí J, López‐Muñoz F, Alamo C, Camarasa X, García‐García P, Pardo A. Effects of Hunziker ME, Suehs BT, Bettinger TL, Crismon ML. based on the structure of venlafaxine, a SNRI that has been shown to pathways (Bannister et al., ; Ossipov et al., ; Lopez-Alvarez et al., )​. Raouf, M., Glogowski, A. J., Bettinger, J. J., and Fudin, J. ().