J Chromatogr. 1977 Sep 1;143(5):499-512.
Determination of amitriptyline and some of its metabolites in blood by high-pressure liquid chromatography.

Kraak JC, Bijster P.

Conditions for the determination of amitriptyline and some of its metabolites in serum on a reversed-phase material (C-8) by high-pressure liquid chromatography with UV detection at 254 nm were systematically investigated. The separation of tricyclic antidepressants is best carried out on a phase system consisting of C-8 bonded-phase material as the stationary phase and water--methanol--dichloromethane--propylamine as the mobile phase. The precision and detection limit of the method and the extraction efficiency were established. A chromatogram of a serum extract from a patient treated with amitriptyline is shown. Serum levels of amitriptyline and its four main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxy-amitriptyline and trans-10-hydroxy-nortriptyline) in a patient receiving 150 mg of amitriptyline daily, are reported.

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Neuropsychopharmacology. 2002 Oct;27(4):554-64.
Role of Gi proteins in the antidepressant-like effect of amitriptyline and clomipramine.

Galeotti N, Bartolini A, Ghelardini C.

Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gi alpha(1), anti-Gi alpha(2), anti-Gi alpha(3), anti-Go alpha(1), anti-Go alpha(2)) on the antidepressant-like effect induced by amitriptyline and clomipramine, was evaluated in the mouse forced swimming test, an animal model of depression. The administration of amitriptyline (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.) produced an increase in the mobility time that was prevented by PTX (0.25 micro g per mouse i.c.v.), administered 11 days before the mouse forced swimming test. Anti-Gi alpha(1) (12.5 micro g per mouse i.c.v.), anti-Gi alpha(2) (12.5 micro g per mouse i.c.v.), anti-Gi alpha(3) (6.25 micro g per mouse i.c.v.), and anti-Go alpha(1) (6.25 micro g per mouse i.c.v.), administered 24 and 18 h before the training session, prevented the amitriptyline and clomipramine increase of the mobility time. By contrast, pretreatment with anti-Go alpha(2) (1.56-12.5 micro g per mouse i.c.v.) never modified the antidepressant-like effect induced by the two investigated compounds. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota-rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole-board test. These results suggest the important role played by Gi(1), Gi(2), Gi(3), and Go(1) protein subtypes and the lack of involvement by Go(2) protein subtype in the transduction mechanism responsible for the antidepressant-like effect produced by amitriptyline and clomipramine.

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J Pharm Pharmacol. 2002 Oct;54(10):1393-8.
Amitriptyline has a dual effect on the conductive properties of the epithelial Na channel.

Pena F, Neaga E, Amuzescu B, Nitu A, Flonta ML.

Department of Animal Physiology and Biophysics, University of Bucharest, Faculty of Biology, Splaiul Independentei 91-95, Bucharest R-76201, Romania.

This study was undertaken with the aim of testing the action of amitriptyline on the epithelial Na channel (ENaC), which belongs to the same family (Deg/ENaC) as ASICs (acid-sensing ion channels) and many other putative members in the brain. We assumed that, having a common protein structure, characterization of the amitriptyline-ENaC interaction could help to elucidate the analgesic mechanism of this tricyclic antidepressant. Na-channel characteristics were derived from the analysis of blocker-induced lorentzian noise produced by amiloride. The effect of amitriptyline, present in the mucosal bathing solution, on the transepithelial short-circuit current (I(sc)) and conductance (G(t)), and on the blocker-induced noise of apical Na channels, was studied on isolated ventral skin of the frog Rana ridibunda. Amitriptyline exerted a dual effect on the macroscopic short-circuit current and conductance of the epithelia, increasing these two parameters in the concentration range 0.1-50 microM, while at higher concentrations (100-1000 microM) it showed an inhibitory action. The decrease in the association rate (k(01)) of amiloride to the apical Na channels from 15.6+/-4.2 microM(-1) s(-1) in control Cl-Ringer to 7.4+/-1.7 microM(-1) s(-1) at 200 microM amitriptyline in a concentration-dependent manner suggests a competitive binding of amitriptyline to the pyrazine ring binding site for amiloride.

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Eur J Pharmacol. 2003 Jan 1;458(1-2):91-9.
Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors.

Honda M, Nishida T, Ono H.

Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, 467-8603, Nagoya, Japan.

The centrally acting muscle relaxant cyclobenzaprine decreases the amplitude of monosynaptic reflex potentials by inhibiting the facilitatory descending serotonergic influences in the spinal cord. Interestingly, the structure of cyclobenzaprine is much similar to those of amitriptyline and cyproheptadine. In the present study, we attempted to elucidate the relationship between 5-HT(2) receptor antagonistic and inhibitory effects of cyclobenzaprine, amitriptyline, cyproheptadine and ketanserin on the spinal reflexes. Cyclobenzaprine, amitriptyline, cyproheptadine, and ketanserin significantly inhibited facilitatory effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on flexor reflexes and mono- and polysynaptic spinal reflex potentials in spinalized rats. In intact rats, these drugs significantly reduced the mono- and polysynaptic reflex potentials. 5-HT depletion significantly prevented the depression of the spinal reflex potentials induced by these drugs. These results suggest that the inhibitory effects of cyclobenzaprine, amitriptyline, and cyproheptadine on mono- and polysynaptic reflex potentials are due to the inhibition of descending serotonergic systems through 5-HT(2) receptors in the spinal cord.

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dal.ca

The local, peripheral administration of antidepressants and excitatory amino acid receptor antagonists can cause analgesia in a number of conditions. The present study examined the effects of combinations of dextromethorphan and ketamine, two clinically used N-methyl-D-aspartate (NMDA) receptor antagonists, with amitriptyline on formalin-evoked behaviors and paw edema. Pretreatment with amitriptyline or dextromethorphan (10-300 nmol) resulted in suppression of flinching behaviors induced by 2.5% formalin, but ketamine had no intrinsic effect. Combination of an inactive dose of dextromethorphan with amitriptyline, and vice versa, resulted in an increase of analgesia so that previously inactive doses now caused significant analgesia. Combinations of multiple doses of ketamine with amitriptyline did not modify the response to amitriptyline. Both dextromethorphan and ketamine increased the paw edema induced by formalin, and this was blocked by low doses of amitriptyline. In the absence of formalin, amitriptyline (1-100 nmol) caused a dose-related suppression of the paw edema produced by dextromethorphan and ketamine. Amitriptyline also blocked paw edema produced by 5-hydroxytryptamine and compound 48/80. Each of the drugs used in this study exerts multiple pharmacological effects. Increased analgesia by drug combinations (amitriptyline/dextromethorphan) could show the involvement of a number of these mechanisms (e.g. NMDA receptor blockade, blockage of sodium channels, blockage of biogenic amine receptors), while a lack of intensification (amitriptyline/ketamine) could reflect occluded actions due to expression of similar actions by the other drug. Paw edema induced by dextromethorphan and ketamine involves inhibition of biogenic amine reuptake, and the ability of amitriptyline to block biogenic amine receptors likely accounts for its inhibiton of these actions. Combinations of these particular agents could represent a method for augmented analgesia and minimization of local adverse reactions.

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Anesth Analg. 2003 Jun;96(6):1707-10, table of contents.
Cutaneous analgesia after transdermal application of amitriptyline versus lidocaine in rats.

Haderer A, Gerner P, Kao G, Srinivasa V, Wang GK.

Department of Anesthesiology, Ried General Hospital, Ried, Austria.

Amitriptyline, a tricyclic antidepressant, has potent local anesthetic properties. However, there is no report of cutaneous analgesic effects after transdermal application. We report here that transdermally applied amitriptyline is more potent than lidocaine in providing cutaneous analgesia in rats. Solutions of amitriptyline base in 50, 100, and 500 mM concentrations were applied as a patch to rats, and their effects were compared with those of lidocaine base at the same concentrations and of the vehicle alone (45% water, 45% isopropyl alcohol, and 10% glycerin). Rats in each test group developed a concentration-dependent cutaneous analgesic block in the areas to which the drugs were applied; however, amitriptyline produced a longer block than lidocaine at the same concentration. The development of amitriptyline as a longer-lasting topical analgesic may improve our ability to treat chronic pain, such as neuropathic pain and neuralgia, and to prevent pain in procedures such as venipuncture. IMPLICATIONS: The tricyclic antidepressant amitriptyline, often used perorally for the management of chronic pain, is shown here to be more potent than lidocaine in providing cutaneous analgesia when applied transdermally with an occlusive dressing in rats.

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partners.org

BACKGROUND: Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. METHODS: The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). RESULTS: In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. CONCLUSIONS: Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.

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