CYP2C19 helps amitriptyline convert to nortriptyline, which is its active metabolite. When it comes to preventing refeeding from nortriptyline, nortriptyline works better than serotonin [1]. In a concentration- and time-maintained manner, nortriptyline hydrochloride (6.25-100 μM; 24-72 hours) dramatically lowers TCCSUP and bladder MBT-2 bladder viability [3]. In TCCSUP and MBT-2 cells, nortriptyline hydrochloride (12.55-100 μM; 24 hours) can cause cell cycle abduction and cytography [3]. Both the inner and outer cells of the pancreas can develop these colon cancer cells when exposed to nortriptyline hydrochloride (12.55-100 μM; 24) [3]. Vital cycle apoptosis of TCCSUP and MBT-2 cells[3] 25 μM, 50 μM, or 100 μM (TCCSUP); 12.5 μM, 25 μM, or 50 μM (MBT-2 cells) Induces apoptosis of TCCSUP and MBT-2 cells for 24 hours TCCSUP and MBT-2 cells[3] 25 μM, 50 μM, or 100 μM (TCCSUP); 12.5 μM, 25 μM, or 50 μM (MBT-2 cells) 24 hours Increases Fas, FasL, FADD, Bax, Bak, and caspase-3. caspase-8, caspase-9, and polymerase (ADP-ribose). decreases the expression of survivin, X-linked apoptosis protein inhibitor, BH3 interaction domain death agonist, Bcl-2, and Bcl-xL.

MBT-2 cell tumor development is inhibited by nortriptyline hydrochloride (10–20 mg/kg; intraperitoneal injection; daily; for 3 weeks) [3].

Cell Viability Assay[3]
Cell Types: Human TCCSUP and Mouse MBT-2 Bladder Cancer Cells
Tested Concentrations: 6.25 μM, 12.5 μM, 25 μM, 50 μM and 100 μM
Incubation Duration: 24, 48 or 72 hrs (hours)
Experimental Results: Cells exhibit Toxic effects on TCCSUP and MBT-2 cells.

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Cell cycle analysis[3]
Cell Types: TCCSUP and MBT-2 Cell
Tested Concentrations: 25 μM, 50 μM or 100 μM (TCCSUP); 12.5 μM, 25 μM or 50 μM (MBT-2 cells)
Incubation Duration: 24 hrs (hours)
Experimental Results: leading to cell cycle arrest in these bladder cancer cells.

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Apoptosis analysis[3]
Cell Types: TCCSUP and MBT-2 Cell
Tested Concentrations: 25 μM, 50 μM or 100 μM (TCCSUP); 12.5 μM, 25 μM or 50 μM (MBT-2 cells)
Incubation Duration: 24 hrs (hours)
Experimental Results: Induction of apoptosis in TCCSUP and MBT-2 cells Western blot analysis [3]
Cell Types: TCCSUP and MBT-2 Cell
Tested Concentrations: 25 μM, 50 μM or 100 μM (TCCSUP); 12.5 μM, 25 μM or 50 μM (MBT- 2 cells)
Incubation Duration: 24 hrs (hours)
Experimental Results: Increased expression of Fas, FasL, FADD, Bax, Bak, and cleaved forms of caspase-3, caspase-8, caspase-9, and

Animal/Disease Models: Adult male C3H/HeN mice (25-30 g; 2-3 months old) were injected with MBT-2 cells [3]
Doses: 10 or 20 mg/kg
Route of Administration: intraperitoneal (ip) injection; daily; three weeks .
Experimental Results: Tumor growth was inhibited in mice vaccinated with MBT-2 cells.

Absorption, Distribution and Excretion
Nortriptyline is readily absorbed in the gastrointestinal tract, but plasma concentrations vary from patient to patient. It undergoes first-pass metabolism, reaching plasma concentrations within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably, ranging from 45% to 85%. Nortriptyline and its metabolites are primarily excreted in the urine, with only a small amount (2%) excreted unchanged. Approximately one-third of a single oral dose is excreted in the urine within 24 hours. A small amount is excreted in the bile. The estimated apparent volume of distribution (Vd) β after intravenous administration is 1633 ± 268 L, ranging from 1460 to 2030 L (21 ± 4 L/kg). Nortriptyline crosses the placenta and is present in breast milk. It is distributed in the heart, lungs, brain, and liver. A study in healthy volunteers showed a mean plasma clearance of 54 L/h for nortriptyline. The mean systemic clearance of nortriptyline was 30.6 ± 6.9 L/h, ranging from 18.6 to 39.6 L/h. /Breast Milk/ Nortriptyline is distributed into breast milk. The concentration of nortriptyline in breast milk appears to be similar to or slightly higher than that in maternal serum.
Peak plasma concentrations occur within 7–8.5 hours after oral administration. Optimal efficacy appears to be associated with plasma concentrations of 50–150 ng/mL.
Clinical pharmacokinetics of amitriptyline were studied in four volunteers after oral administration of 75 mg. Peak plasma concentrations of amitriptyline ranged from 10.8 to 43.7 ng/mL. Its elimination was biphasic and conformed to first-order kinetics. The mean elimination half-life was 36.1 hours. The mean first-pass metabolism of amitriptyline was estimated to be 60%. Despite peak concentrations of the metabolite nortriptyline ranging from only 5.9 to 12.3 ng/mL, a significant amount of metabolite was generated.
Although tricyclic antidepressants (TCAs) are widely accepted for the treatment of pregnancy-related depression, their pharmacokinetic characteristics during pregnancy remain unclear. This study aimed to investigate the transplacental transport of amitriptyline (AMI) and its major active metabolite nortriptyline (NOR) in ex vivo perfused human placentas. Nine full-term human placentas were immediately obtained with the mothers' consent, and individual placental villi were perfused non-circulatingly for 2 hours. AMI (200 ng/ml) and NOR (150 ng/ml) were added to the maternal reservoir, and their presence in fetal circulation was monitored for 2 hours using antipyrine as a reference compound. The concentrations of AMI and NOR were determined by high-performance liquid chromatography (HPLC), and the concentration of antipyrine was determined by spectrophotometry. The mean (standard deviation) transplacental transport rates (TPT(SS)%) for AMI and NOR were 8.2 (2.3)% and 6.5 (1.8)%, respectively, calculated as the ratio of the steady-state concentration on the fetal venous side to the maternal arterial side. The TPTs for AMI and NOR were 81% and 62% of the freely diffused antipyrine, respectively. The absolute dose fraction (TPT(A)) across the placenta was slightly higher in the AMI group (7.7%) than in the NOR group (5.7%) (P=0.037). In all perfusion experiments, the AMI group reached fetal steady-state within 30 minutes, while the NOR group reached steady-state within 50 minutes. During the 2-hour perfusion, placental activity was maintained, the pH of the perfusion solution remained constant, the fetal arterial perfusion pressure was stable, and antipyrine transport was stable. Both AMI and NOR can cross the human placenta. However, the fetal exposure of NOR may be slightly lower than that of AMI, possibly due to the higher lipophilicity of AMI.

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Metabolism/Metabolites
Noretriptyline is metabolized in the liver via demethylation and hydroxylation, followed by conjugation with glucuronic acid. CYP2D6 plays a crucial role in the metabolism of noretriptyline, with CYP1A2, CYP2C19, and CYP3A4 also involved. The major active metabolite is 10-hydroxynortriptyline, existing in both cis and trans forms, with the trans form being more potent. 10-hydroxynortriptyline is the most common metabolite in plasma. Most other metabolites are conjugated metabolites with lower potency.
This study investigated the biotransformation of amitriptyline to its demethylated product, noretriptyline, in vitro using human liver microsomes from four different donors. These donors were pre-screened to reflect different metabolic rates. The relationship between reaction rate and substrate concentration conformed to an S-type Vmax model. Vmax ranged from 0.42 to 3.42 nmol/mg/min, and Km ranged from 33 to 89 μM amitriptyline. Ketoconazole is a potent inhibitor of N-demethylation, with an average Ki value of 0.11 ± 0.013 μM… while the CYP2D6 inhibitor quinidine (at concentrations up to 50 μM) and the CYP1A2 inhibitor α-naphthylflavonoid (at concentrations up to 5 μM, effective only at low concentrations) showed no effect. All tested selective serotonin reuptake inhibitors inhibited the formation of nortriptyline, with mean Ki values of 4.37 (± 3.38) uM for sertraline, 5.46 (± 1.95) uM for norsertraline, 9.22 (± 3.69) uM for fluvoxamine, 12.26 (± 5.67) uM for norfluoxetine, 15.76 (± 5.50) uM for paroxetine, and 43.55 (± 18.28) uM for fluoxetine. A polyclonal rabbit antibody targeting rat liver CYP3A1 inhibited N-demethylation of amitriptyline in antibody/microsomal protein ratios ranging from 1:1 to 10:1, with an asymptotic maximum of 60%. It has been reported that the metabolic distribution of antidepressants and antipsychotics is significantly influenced by cytochrome P450 (CYP) 2D6 isoenzymes. The two most studied antidepressants are amitriptyline and imipramine. Studies have shown that the conversion of amitriptyline to nortriptyline and the metabolism of nortriptyline to its 10-hydroxy metabolite are both influenced by the 2D6 isoenzyme. This study also investigated the stability of amitriptyline, nortriptyline, desipramine, and imipramine in formalin-fixed human liver tissue and formalin solution. The contents of tricyclic drugs and their major demethylated metabolites in frozen liver were determined and compared with those in formalin-fixed and preserved liver. The results showed that in the formalin environment, some secondary amine nortriptyline was methylated to the corresponding tertiary amine amitriptyline, and desipramine was methylated to imipramine. Nortriptyline was not detected in most cases, suggesting that its degradation rate may be faster than that of desipramine. There was no consistent proportional relationship between drug concentrations in frozen liver tissue, formalin-preserved liver tissue, or formalin solution. The methylation rate of secondary amines could not be quantified. Preserving liver tissue in formalin solution at room temperature can cause drug leaching into the formalin solution. The residual time of the test drug in formalin-fixed liver and formalin culture medium can be up to 22 months. Known metabolites of nortriptyline include desmethylnortriptyline and E-10-hydroxynortriptyline. Nortriptyline is a known metabolite of amitriptyline. Like other tricyclic antidepressants (TCAs), nortriptyline is metabolized via the same hepatic metabolic pathway. Elimination pathway: Approximately one-third of a single oral dose is excreted in the urine within 24 hours. A small amount of the drug is excreted in the bile. Half-life: 16 to over 90 hours. The average half-life of nortriptyline in the plasma of healthy volunteers is approximately 26 hours, but is reported to range from 16 to 38 hours. One study mentioned an average half-life of approximately 39 hours. The plasma half-life of nortriptyline ranges from 16 to over 90 hours. Clinical pharmacokinetics were studied in four volunteers after oral administration of 75 mg amitriptyline. ...The mean elimination half-life was 36.1 hours. ...

Hepatotoxicity
It has been reported that up to 16% of patients receiving tricyclic antidepressants experience abnormal liver function, but elevations exceeding three times the upper limit of normal are uncommon. Transaminase abnormalities are usually mild, asymptomatic, and transient, and can be reversed with continued medication. Nortriptyline has been reported to cause rare, clinically significant acute liver injury. Jaundice typically appears within 2 to 3 months of starting nortriptyline, with a predominantly hepatocellular enzyme profile. Several cases of acute hepatotoxicity caused by nortriptyline have been reported, presenting with significantly elevated serum transaminase levels and acute liver failure. Hypersensitivity and autoimmune signs and symptoms are usually absent. Probability Score: C (Possibly a rare cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Because the content of nortriptyline in breast milk is low, the amount ingested by infants is very small and usually undetectable in infant serum. However, less active metabolites are usually detectable at low concentrations in infant serum. No immediate side effects have been reported, and limited follow-up studies have not found any adverse effects on infant growth and development. The safety rating system considers the use of nortriptyline with caution during lactation to be feasible. Most authoritative reviewers consider nortriptyline to be one of the first-line antidepressants during lactation.
◉ Effects on breastfed infants
At least 44 infants have been reported to be exposed to nortriptyline through breast milk, with no adverse reactions reported when mothers took daily doses ranging from 25 to 175 mg. The time of first exposure ranged from the neonatal period to 3.5 months. Follow-up time ranged from observation of infants to comprehensive developmental testing.
Of the aforementioned infants, 27 underwent formal testing between 15 and 71 months of age, and the results showed normal growth and development. Two small controlled studies found that other tricyclic antidepressants in breast milk had no adverse effects on infant development.
◉ Effects on Lactation and Breast Milk
Noretropin usually only slightly increases serum prolactin levels, but in rare cases can cause galactorrhea in non-pregnant, non-lactating patients.
An observational study investigated the outcomes of 2,859 women who had taken antidepressants in the two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants in all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in the third trimester were 75% less likely to breastfeed at discharge. Mothers who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. The specific antidepressants used by the mothers were not specified. A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women who took antidepressants in late pregnancy (n = 575), women with mental illness but not taking antidepressants (n = 1552), and mothers not diagnosed with mental illness (n = 30,535). Results showed that women who took antidepressants were 37% less likely to breastfeed at discharge than women not diagnosed with mental illness, but there was no significant difference in the likelihood of breastfeeding compared to untreated mothers with mental illness. None of the mothers were taking nortriptyline. A study of 80,882 Norwegian mother-infant pairs from 1999 to 2008 showed that 392 women reported starting antidepressants postpartum, and another 201 women reported starting antidepressants during pregnancy. Compared to a control group not exposed to antidepressants, taking antidepressants in late pregnancy was associated with a 7% lower rate of breastfeeding initiation, but had no effect on the duration of breastfeeding or the rate of exclusive breastfeeding. Compared to a control group that had not been exposed to antidepressants, starting or restarting antidepressants postpartum was associated with a 63% decrease in breastfeeding rates at 6 months, a 51% decrease in any breastfeeding rate, and a 2.6-fold increased risk of abruptly stopping breastfeeding. The study did not mention any specific antidepressant.
◈ What is nortriptyline?
Nerotriptyline is a medication used to treat depression. It belongs to the tricyclic antidepressant class. Nortriptyline has also been used to treat attention deficit hyperactivity disorder (ADHD), eating disorders, irritable bowel syndrome, and pain. Brand names for nortriptyline include Aventyl® and Pamelor®. For more information on depression, please see our fact sheet: https://mothertobaby.org/fact-sheets/depression-pregnancy/. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to talk to your healthcare provider before changing your medication regimen. Some people may experience a relapse of symptoms if they stop taking their medication during pregnancy. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy.
◈ I am taking nortriptyline. Will taking nortriptyline affect my pregnancy?
It is currently unclear whether nortriptyline affects pregnancy.
◈ Does taking nortriptyline increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There is currently no research indicating that nortriptyline increases the risk of miscarriage.
◈ Does taking nortriptyline increase the risk of birth defects?
There is a 3-5% risk of birth defects in every pregnancy, known as the background risk. Based on the reviewed studies, it is unclear whether nortriptyline increases the risk of birth defects above the background risk.
◈ Does taking nortriptyline during pregnancy increase the risk of other pregnancy-related problems?
There is currently no research indicating that nortriptyline increases the risk of pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). One report showed that an infant who took nortriptyline during pregnancy developed urinary retention (the bladder could not completely empty).
◈ I need to take nortriptyline throughout my pregnancy. Will it cause my baby to experience withdrawal symptoms after birth?
Use of tricyclic antidepressants (including nortriptyline) during pregnancy may cause temporary symptoms in newborns shortly after birth. These symptoms are sometimes called withdrawal symptoms. These symptoms include colic, cyanosis (blue skin), difficulty breathing, and irritability. In most cases, these symptoms disappear within a few days and do not have long-term health effects. Not all infants exposed to tricyclic antidepressants will experience these symptoms. It is important that your healthcare provider knows you are taking nortriptyline so that your baby can receive optimal care if symptoms occur.
◈ Will taking nortriptyline during pregnancy affect a child's future behavior or learning?
One study tested 80 children (aged 16-86 months) who were exposed to tricyclic antidepressants in early pregnancy. Eight of the children had been exposed to nortriptyline. Compared to children exposed to other antidepressants (fluoxetine) and children who were not exposed to antidepressants during pregnancy, these children exposed to nortriptyline showed no difference in IQ, language, or behavior.
◈ Breastfeeding while taking nortriptyline:
A small amount of nortriptyline passes into breast milk. A few case reports have shown that nortriptyline has no side effects or negative impacts on infant growth and development. Please consult your healthcare provider about all questions regarding breastfeeding.
◈ Does nortriptyline affect fertility (the ability to impregnate a partner) or increase the risk of birth defects if a man takes it?
Based on reviewed studies, it is unclear whether nortriptyline affects male fertility. Some studies have reported that nortriptyline reduces male libido and causes sexual dysfunction, which may affect fertility. However, these effects may be the result of underlying medical conditions, other factors, or a combination of factors, and not necessarily caused by the drug itself. There are currently no studies assessing whether nortriptyline increases the risk of birth defects (above background risk). Generally, exposure to medications by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please refer to MotherToBaby's "Paternal Exposure" information sheet at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
The plasma protein binding rate of nortriptyline is approximately 93%.

[1]. Dean L. Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype. Biotechnology Information (US); 2012-2017 Mar 23.

[2]. Repurposing Autophagy Regulators in Brain Tumors [published online ahead of print, 2022 Feb 18]. Int J Cancer. 2022;10.1002/ijc.33965.

[3]. Nortriptyline induces mitochondria and death receptor-mediated apoptosis in bladder cancer cells and inhibits bladder tumor growth in vivo. Eur J Pharmacol. 2015 Aug 15:761:309-20.

Nortriptyline is an organic tricyclic compound with the structure 10,11-dihydro-5H-dibenzo[a,d][7]annulene, with a 3-(methylamino)propylidene substitution at the 5-position. It is the active metabolite of amitriptyline. Nortriptyline has various pharmacological effects, including as a drug metabolite, antidepressant, adrenergic reuptake inhibitor, analgesic, antitumor drug, and apoptosis inducer. It is an organic tricyclic compound and also a secondary amine. Its function is related to amitriptyline. Nortriptyline is derived from the hydride of dibenzo[a,d][7]annulene. Nortriptyline hydrochloride is the active metabolite of amitriptyline and is a tricyclic antidepressant (TCA). It is used to treat major depressive disorder and also to treat chronic pain and other conditions (off-label use). Nortriptyline is a tricyclic antidepressant. Nortriptyline is a tricyclic antidepressant and is also used for smoking cessation. Nortriptyline can cause mild and transient increases in serum enzymes, but rarely causes clinically significant acute or chronic cholestatic liver injury. Nortriptyline has been reported to be used in the Berlandieri region of Senegal, with relevant data available. Nortriptyline is a tricyclic antidepressant used for short-term treatment of various types of depression. Nortriptyline blocks presynaptic receptors of norepinephrine, thereby blocking the reuptake of this neurotransmitter and increasing its concentration in the synaptic cleft of the central nervous system. Nortriptyline also binds to alpha-adrenergic receptors, histaminergic receptors, and cholinergic receptors. Long-term use of nortriptyline leads to downregulation of adrenergic receptors due to enhanced stimulation of these receptors. Nortriptyline hydrochloride is the N-demethylated active metabolite of amitriptyline, a dibenzocyclohepten derivative tricyclic antidepressant (TCA). The structure of tricyclic antidepressants (TCAs) is similar to that of phenothiazines, both containing a tricyclic ring system with an alkylamine substituent attached to the central ring. In non-depressive patients, nortriptyline does not affect mood or arousal but may cause sedation. In depressive patients, nortriptyline has a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Secondary amine TCAs (such as nortriptyline) are more potent inhibitors of norepinephrine reuptake than tertiary amine TCAs (such as amitriptyline). Tricyclic antidepressants (TCAs) also downregulate β-adrenergic receptors in the cerebral cortex and sensitize postsynaptic serotonergic receptors with long-term use. The antidepressant effect of TCAs is thought to be due to an overall enhancement of serotonergic neurotransmission. TCAs also block histamine H1 receptors, α1-adrenergic receptors, and muscarinic receptors, which explains their sedative, hypotensive, and anticholinergic effects (e.g., blurred vision, dry mouth, constipation, urinary retention). For a complete list of side effects, see the Toxicity section below. Nortriptyline has milder anticholinergic and sedative side effects compared to tertiary amine TCAs such as amitriptyline and clomipramine. Nortriptyline can be used to treat depression, chronic pain (unapproved indication), irritable bowel syndrome (unapproved indication), diabetic neuropathy (unapproved indication), post-traumatic stress disorder (unapproved indication), and migraine prevention (unapproved indication). Nortriptyline is a metabolite of amitriptyline and is also used as an antidepressant. Nortriptyline is used to treat major depressive disorder, dysphoric mood, and atypical depression. See also: Nortriptyline hydrochloride (salt form).

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Drug Indications
Noretriptyline is indicated for the relief of symptoms of major depressive disorder (MDD). Some non-indications for this drug include the treatment of chronic pain, myofascial pain, neuralgia, and irritable bowel syndrome.
FDA Label

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Mechanism of Action
While the prescribing information does not explicitly state the specific mechanism of action of nortriptyline, it is generally believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin on neuronal membranes or acts on β-adrenergic receptors. Its inhibition of norepinephrine reuptake is more selective, which may explain the more significant symptom improvement after nortriptyline treatment. Tricyclic antidepressants do not inhibit monoamine oxidase or affect dopamine reuptake. Like other tricyclic antidepressants, nortriptyline has affinity for other receptors, including muscarinic acetylcholine receptors, histamine receptors, and serotonin receptors.
To investigate the mechanism of imipramine-induced adverse reactions…we induced such reactions in rats by intraperitoneal injection of imipramine (5–40 mg/kg) three times at 24, 5, and 1 hour before testing, and compared the occurrence of these reactions with similar treatments using specific norepinephrine and serotonergic reuptake inhibitors (nortriptyline (10 or 30 mg/kg, intraperitoneal injection), citalopram (0.5–5.0 mg/kg, intraperitoneal injection)). This preliminary study suggests that these reactions are mediated by the norepinephrine-mediated effect. This study compared the effects of equal doses of amitriptyline and nortriptyline on serotonin, dopamine, and their major acidic metabolite concentrations in five different brain regions and analyzed their relationship with inbred mouse strains. The results showed that amitriptyline increased serotonin levels in the brain regions of albino BALB/c mice more effectively than nortriptyline. Both drugs increased serotonin levels in certain brain regions of black C57BL/6 mice, but decreased 5-hydroxyindoleacetic acid (5-HIAA) levels in the brain. These results indicate strain-dependent differences in the increase of serotonin metabolism in different mouse strains, which may explain the higher incidence of amitriptyline-induced sedation and seizures. The study found that BALB/c mice were more sensitive to the effects of both drugs on dopamine and its main acidic metabolites than C57BL/6 mice, with amitriptyline showing greater potency in specific brain regions than nortriptyline. Data suggest increased dopamine turnover, particularly in brain regions related to motor function and posture, which may explain the extrapyramidal disorders induced by tricyclic antidepressants. The results also suggest that the C57BL/6 mouse strain may have experimental value for studying the mechanisms of adverse reactions associated with sedation and motor disorders induced by tricyclic antidepressants, and the relationship between these reactions and genetic susceptibility. Neuropathic pain refers to pain directly caused by damage or disease of the somatosensory system. Neuropathic pain is typically chronic and difficult to treat. Some antidepressants are first-line treatments for neuropathic pain. The norepinephrine recruited by antidepressants after acting on reuptake transporters is thought to exert its effects through β2-adrenergic receptors (β2-ARs), thus producing the observed therapeutic effects. However, the complex downstream mechanisms mediating this effect remain to be elucidated. This study, using a mouse model of neuropathic pain, demonstrated that the effects of antidepressants on neuropathic hyperalgesia involve the peripheral nervous system and inhibit the production of the cytokine tumor necrosis factor-α (TNFα). The anti-hyperalgesic effect of nortriptyline disappeared after peripheral sympathectomy but not after damage to the central descending norepinephrine pathway. More specifically, we found that norepinephrine recruited by antidepressants acts on β2-ARs expressed on non-neuronal satellite cells within the dorsal root ganglion. Activation of β2-adrenergic receptors (β2-ARs) reduces neuropathy-induced membrane-bound TNFα production, thereby alleviating neuropathic hyperalgesia. This indirect anti-TNFα effect has been observed in the tricyclic antidepressant nortriptyline, the selective serotonin and norepinephrine reuptake inhibitor venlafaxine, and the β2-AR agonist terbutaline. Our data reveal a unique therapeutic mechanism that may open new avenues for research in the treatment of painful peripheral neuropathy.

C19H22CLN

299.842

299.144

894-71-3

Nortriptyline;72-69-5;Nortriptyline-d3 hydrochloride;203784-52-5

4543

White to off-white solid powder

403.4ºC at 760 mmHg

217-220ºC

194.9ºC

5.019

1

1

3

20

307

0

Cl.C1C=C2/C(/C3C(CCC2=CC=1)=CC=CC=3)=C\CCNC

Nortriptyline HCl Lilly 38489 N 7048NortriptylineAllegron DesmethylamitriptylinAventyl Desitriptyline

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~83.33 mg/mL (~277.91 mM)
H2O : ~7.14 mg/mL (~23.81 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)