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 with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%.
Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.
The apparent volume of distribution (Vd)β, estimated after intravenous administration is 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver.
The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour.
/MILK/ Nortriptyline is distributed into milk. Nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum.
Peak plasma concentrations occur within 7-8.5 hours after oral administration. Optimal response to the drug appears to be associated with plasma concentrations of 50-150 ng/mL.
The clinical pharmacokinetics of amitriptyline were studied in four volunteers after the oral administration of 75 mg. Peak amitriptyline plasma concentrations ranged from 10.8 to 43.7 ng/mL. The disappearance was biphasic and followed first-order kinetics. The mean elimination half-life was 36.1 hours. The mean estimated first-pass metabolism of amitriptyline was 60 per cent. Significant quantities of the metabolite, nortriptyline, were produced although peak concentrations ranged from only 5.9 to 12.3 ng/mL.
Although tricyclic antidepressants (TCAs) have gained wide acceptance for use in the treatment of depression in pregnant women, their pharmacokinetics during pregnancy have been poorly characterized. The aim of the present study was to investigate the transplacental transfer of amitriptyline (AMI) and its main active metabolite nortriptyline (NOR) in isolated perfused human placenta. Nine term human placentae were obtained immediately after delivery with maternal consent and a 2-h non-recirculating perfusion of a single placental cotyledon was performed. AMI (200 ng/ml) and NOR (150 ng/ml), with antipyrine as a reference compound, were added to the maternal reservoir and their appearance to the fetal circulation was followed for 2 h. AMI and NOR concentrations were measured by high performance liquid chromatography (HPLC) and antipyrine concentrations spectrophotometrically. The mean (SD) transplacental transfers (TPT(SS)%) for AMI and NOR were 8.2 (2.3)% and 6.5 (1.8)%, respectively, calculated as the ratio between the steady-state concentrations in fetal venous and maternal arterial sides. The TPTs of AMI and NOR were 81% and 62% of the freely diffusable antipyrine. The absolute fraction of the dose that crossed the placenta (TPT(A)) was moderately, but significantly higher for AMI (7.7%) than for NOR (5.7%) (P=0.037). In all perfusions, steady state at the fetal side was reached by 30 min for AMI and by 50 min for NOR in the fetal side. The viability of the placentae was retained during the 2-h perfusion, as evidenced by unchanged pH of the perfusate and by stable perfusion pressures in fetal artery and stable antipyrine transfer. Both AMI and NOR cross the human placenta. However, the fetal exposure with NOR may be somewhat smaller compared with AMI, probably due to the higher lipophilicity of AMI.

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Metabolism / Metabolites
Nortriptyline is metabolized via demethylation and hydroxylation in the liver followed by glucuronic acid conjugation. CYP2D6 plays a large role in nortriptyline metabolism, with contributions from CYP1A2, CYP2C19 and CYP3A4. The main active metabolite is 10-hydroxynortriptyline exists in both cis and a trans form, with the trans form is higher in potency. 10-hydroxynortriptyline is the most frequently found in the plasma. Most of the other metabolites are conjugated, and are less potent.
Biotransformation of amitriptyline to its demethylated product nortriptyline was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concn was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 uM amitriptyline. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 + or - 0.013 uM ... whereas quinidine (up to 50 uM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 uM), a CYP1A2 inhibitor only at low concn, showed no effect. All selective serotonin reuptake inhibitors tested had an inhibitory effect on the formation of nortriptyline, with mean Ki values of 4.37 (+ or - 3.38) uM for sertraline, 5.46 (+ or - 1.95) uM for desmethylsertraline, 9.22 (+ or - 3.69) uM for fluvoxamine, 12.26 (+ or - 5.67) uM for norfluoxetine, 15.76 (+ or - 5.50) uM for paroxetine, and 43.55 (+ or - 18.28) uM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein ratios varying from 1:1 to 10:1, inhibited N-demethylation of amitriptyline to an asymptotic max of 60%.
The metabolic disposition of the antidepressants and antipsychotics has been reported to be significantly influenced by the cytochrome P450 (CYP) 2D6 isozyme. The two most studied antidepressants are amitriptyline and imipramine. Amitriptyline conversion to nortriptyline and nortriptyline metabolism to its 10-hydroxymetabolite were shown to be influenced by the 2D6 isozyme.
The stability of amitriptyline, nortriptyline, desipramine and imipramine in formalin-fixed human liver tissue and formalin soln was investigated. The levels of the tricyclic and its primary demethylated metabolite in the frozen liver were determined and compared with levels obtained in the formalin-fixed liver and formalin soln in which the liver was stored. It was obvious that some methylation of the secondary amine, nortriptyline, to the corresponding tertiary amine, amitriptyline, and of desipramine to imipramine took place in the formalin environment. Nortriptyline was not detected in most cases, suggesting that it may degrade more rapidly than desipramine. There was no consistent ratio between the concn of the drug in the frozen liver tissue versus formalin-preserved tissue or versus formalin soln. The methylation rates of the secondary amines could not be quantitated. Storage of the liver tissue in formalin at room temp resulted in leaching of the drugs into the formalin soln. The drugs tested may be detected for up to 22 mo in the formalin-fixed liver and in the formalin medium.
Nortriptyline has known human metabolites that include demethylnortriptyline and E-10-hydroxynortriptyline.
Nortriptyline is a known human metabolite of amitriptyline.
Undergoes hepatic metabolism via the same pathway as other TCAs.
Route of Elimination: Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.
Half Life: 16 to 90+ hours

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Biological Half-Life
The average plasma half-life of nortriptyline in healthy volunteers is about 26 hours, but is said to range from 16 to 38 hours. One study mentions a mean half-life of about 39 hours.
The plasma half-life of nortriptyline ranges from 16 to more than 90 hours.
The clinical pharmacokinetics of amitriptyline were studied in four volunteers after the oral administration of 75 mg. ... The mean elimination half-life was 36.1 hours. ...

Hepatotoxicity
Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to nortriptyline. The onset of jaundice is usually within 2 to 3 months of starting nortriptyline and the predominant enzyme pattern has been hepatocellular. Several acute instances of nortriptyline hepatotoxicity with marked elevations in serum aminotransferase levels and acute liver failure have been described. Signs and symptoms of hypersensitivity and autoimmunity are usually not present.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low levels of nortriptyline in breastmilk, amounts ingested by the infant are small and usually not been detected in the serum of the infant, although the less active metabolites are often detectable in low levels in infant serum. Immediate side effects have not been reported and a limited amount of follow-up has found no adverse effects on infant growth and development. A safety scoring system finds nortriptyline use to be possible with caution during breastfeeding. Most authoritative reviewers consider nortriptyline one of the preferred antidepressants during breastfeeding.
◉ Effects in Breastfed Infants
At least 44 infants have been reported to have been exposed to nortriptyline in breastmilk with no reports of adverse reactions with maternal dosages from 25 to 175 mg daily. The time of initial exposure ranged from the immediate newborn period to 3.5 months. The follow-up ranged from observation of the infants to full developmental testing.
Twenty-seven of the above infants were tested formally between 15 to 71 months and found to have normal growth and development. Two small controlled studies found that other tricyclic antidepressants in breastmilk also had no adverse effect on infant development.
◉ Effects on Lactation and Breastmilk
Nortriptyline usually increases serum prolactin only slightly, but has caused galactorrhea in nonpregnant, nonnursing patients rarely.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking nortriptyline.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
◈ What is nortriptyline?
Nortriptyline is a medication that has been used to treat depression. It is part of a group of medications called tricyclic antidepressants. Nortriptyline has also been used to treat attention deficit hyperactivity disorder (ADHD), eating disorders, irritable bowel syndrome, and pain. Some brand names for nortriptyline are Aventyl® and Pamelor®. For more information on depression, please see our fact sheet at https://mothertobaby.org/fact-sheets/depression-pregnancy/.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Some people may have a return of their symptoms (relapse) if they stop this medication during pregnancy. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take nortriptyline. Can it make it harder for me to get pregnant?
It is not known if nortriptyline can make it harder to get pregnant.
◈ Does taking nortriptyline increase the chance for miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if nortriptyline increases the chance for miscarriage.
◈ Does taking nortriptyline increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, it is not known if nortriptyline increases the chance for birth defects above the background risk.
◈ Does taking nortriptyline in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if nortriptyline increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).There is one report of urinary retention (when the bladder cannot empty all the urine) in an infant exposed to nortriptyline during pregnancy.
◈ I need to take nortriptyline throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?
The use of tricyclic antidepressants (including nortriptyline) during pregnancy may cause temporary symptoms in newborns soon after birth. These symptoms are sometimes referred to as withdrawal. The symptoms include colic, cyanosis (skin looks blue), breathing problems, and irritability. In most cases the symptoms go away in a few days without long-term health effects. Not all babies exposed to tricyclic antidepressants will have these symptoms. It is important that your healthcare providers know you are taking nortriptyline so that if symptoms occur your baby can get the care that is best for them.
◈ Does taking nortriptyline in pregnancy affect future behavior or learning for the child?
One study tested 80 children (ages 16 - 86 months) who were exposed to tricyclic antidepressants in the first trimester of pregnancy. Eight of those children had been exposed to nortriptyline. The exposed children showed no differences in IQ, language, or behavior compared to children with exposure to a different antidepressant (fluoxetine) and children who were not exposed to antidepressants during pregnancy.
◈ Breastfeeding while taking nortriptyline:
Nortriptyline passes into breastmilk in small amounts. A limited number of cases have reported no side effects or negative effects on infant growth and development. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes nortriptyline, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Based on the studies reviewed, it is not known if nortriptyline could affect male fertility. Some studies have reported that nortriptyline lowers sex drive and causes sexual dysfunction in males, which could affect the ability to conceive a pregnancy. However, these effects could be from the underlying condition, other factors, or a combination of factors and not necessarily the medication.Studies have not been done to see if nortriptyline could increase the chance of birth defects above te background risk. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
The plasma protein binding 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 that is 10,11-dihydro-5H-dibenzo[a,d][7]annulene substituted by a 3-(methylamino)propylidene group at position 5. It is an active metabolite of amitriptyline. It has a role as a drug metabolite, an antidepressant, an adrenergic uptake inhibitor, an analgesic, an antineoplastic agent and an apoptosis inducer. It is an organic tricyclic compound and a secondary amine. It is functionally related to an amitriptyline. It derives from a hydride of a dibenzo[a,d][7]annulene.
Nortriptyline hydrochloride, the active metabolite of [amitriptyline], is a tricyclic antidepressant (TCA). It is used in the treatment of major depression and is also used off-label for chronic pain and other conditions.
Nortriptyline is a Tricyclic Antidepressant.
Nortriptyline is a tricyclic antidepressant that is also used in smoking cessation. Nortriptyline can cause mild and transient serum enzyme elevations and is rare cause of clinically apparent acute and chronic cholestatic liver injury.
Nortriptyline has been reported in Senegalia berlandieri with data available.
Nortriptyline is a tricyclic antidepressant agent used for short-term treatment of various forms of depression. Nortriptyline blocks the norepinephrine presynaptic receptors, thereby blocking the reuptake of this neurotransmitter and raising the concentration in the synaptic cleft in the CNS. Nortriptyline also binds to alpha-adrenergic, histaminergic and cholinergic receptors. Long-term treatment with nortriptyline produces a downregulation of adrenergic receptors due to the increased stimulation of these receptors.
Nortriptyline hydrochloride, the N-demethylated active metabolite of amitriptyline, is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, nortriptyline does not affect mood or arousal, but may cause sedation. In depressed individuals, nortriptyline exerts 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. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine-H₁ receptors, α₁-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Nortriptyline exerts less anticholinergic and sedative side effects compared to the tertiary amine TCAs, amitriptyline and clomipramine. Nortriptyline may be used to treat depression, chronic pain (unlabeled use), irritable bowel syndrome (unlabeled use), diabetic neuropathy (unlabeled use), post-traumatic stress disorder (unlabeled use), and for migraine prophylaxis (unlabeled use).
A metabolite of AMITRIPTYLINE that is also used as an antidepressive agent. Nortriptyline is used in major depression, dysthymia, and atypical depressions.
See also: Nortriptyline Hydrochloride (has salt form).

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Drug Indication
Nortriptyline is indicated for the relief of the symptoms of major depressive disorder (MDD). Some off-label uses for this drug include treatment of chronic pain, myofascial pain, neuralgia, and irritable bowel syndrome.
FDA Label

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Mechanism of Action
Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other receptors.
The mechanism of adverse imipramine-induced reactions ... was investigated by precipitating such reactions in rats with three injections (ip) of imipramine (5-40 mg/kg) at 24, 5, and 1 hr before testing, and comparing their occurrence with comparable treatments using specific noradrenergic and serotonergic reuptake inhibitors (nortriptyline (10 or 30 mg/kg, ip), citalopram (0.5-5.0 mg/kg, ip)). This initial study indicated that these reactions were mediated by imipramine's noradrenergic effects.
The effect of equal-dose regimens of amitriptyline and nortriptyline on the concn of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline incr to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs incr serotonin levels but decr cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential incr in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an incr in dopamine turnover particularly in brain areas assoc with motor function and posture which may account for tricyclic antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.
Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through beta2-adrenoceptors (beta2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor a (TNFa) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on beta2-ARs expressed by non-neuronal satellite cells. This stimulation of beta2-ARs decreases the neuropathy-induced production of membrane-bound TNFa, resulting in relief of neuropathic allodynia. This indirect anti-TNFa action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the beta2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies.

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.)