BACKGROUND: The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. METHODS: Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. RESULTS: Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. CONCLUSIONS: The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.
Adenosine ; Amitriptyline ; Animals ; Antidepressive Agents, Tricyclic ; Cyclic AMP Response Element-Binding Protein ; Cytokines ; Humans ; Hyperalgesia ; Immunoblotting ; Ligation ; Male ; Neuralgia ; Phosphotransferases ; Polymerase Chain Reaction ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P1 ; Spinal Nerves

BACKGROUND: Use of antidepressant medications has been linked to detrimental impacts on bone mineral density and osteoporosis; however, the cellular basis behind these observations remains poorly understood. The effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. In this study, we hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism. METHODS: Human MSCs (hMSCs) were committed to differentiate when either adipogenic or osteogenic media was added, supplemented with five increasing concentrations of amitriptyline (0.001–10 µM), venlafaxine (0.01–25 µM), or fluoxetine (0.001–10 µM). Alizarin red staining (mineralization), alkaline phosphatase (osteoblastogenesis), and oil red O (adipogenesis) assays were performed at timed intervals. In addition, cell viability was assessed using a MTT. RESULTS: We found that fluoxetine had a significant inhibitory effect on mineralization. Furthermore, adipogenic differentiation of hMSC was affected by the addition of amitriptyline, venlafaxine, and fluoxetine to the media. Finally, none of the tested medications significantly affected cell survival. CONCLUSIONS: This study showed a divergent effect of three antidepressants on hMSC differentiation, which appears to be independent of class and dose. As fluoxetine and amitriptyline, but not venlafaxine, affected both osteoblastogenesis and adipogenesis, this inhibitory effect could be associated to the high affinity of fluoxetine to the serotonin transporter system.
Adipogenesis ; Alkaline Phosphatase ; Amitriptyline ; Antidepressive Agents ; Bone Density ; Cell Survival ; Fluoxetine ; Humans ; Mesenchymal Stromal Cells ; Metabolism ; Miners ; Osteoblasts ; Osteoporosis ; Serotonin Plasma Membrane Transport Proteins ; Venlafaxine Hydrochloride

Amitriptyline, a tricyclic antidepressant, is commonly used to treat depression and neuropathic pain, but its mechanism is still unclear. We tested the effect of amitriptyline on 5-hydroxytryptamine 3 (5-HT₃) receptor currents and studied its blocking mechanism because the clinical applications of amitriptyline overlapped with 5-HT₃ receptor therapeutic potentials. Using a whole-cell voltage clamp method, we recorded the currents of the 5-HT₃ receptor when 5-HT was applied alone or co-applied with amitriptyline in cultured NCB-20 neuroblastoma cells known to express 5-HT₃ receptors. To elucidate the mechanism of amitriptyline, we simulated the 5-HT₃ receptor currents using Berkeley Madonna® software and calculated the rate constants of the agonist binding and receptor transition steps. The 5-HT₃ receptor currents were inhibited by amitriptyline in a concentration-dependent, voltage-independent manner, and a competitive mode. Amitriptyline accelerated the desensitization of the 5-HT₃ receptor. When amitriptyline was applied before 5-HT treatment, the currents rose slowly until the end of 5-HT treatment. When amitriptyline was co-applied with 5-HT, currents rose and decayed rapidly. Peak current amplitudes were decreased in both applications. All macroscopic currents recorded in whole cell voltage clamping experiments were reproduced by simulation and the changes of rate constants by amitriptyline were correlated with macroscopic current recording data. These results suggest that amitriptyline blocks the 5-HT₃ receptor by close and open state blocking mechanisms, in a competitive manner. We could expand an understanding of pharmacological mechanisms of amitriptyline related to the modulation of a 5-HT₃ receptor, a potential target of neurologic and psychiatric diseases through this study.
Amitriptyline* ; Constriction ; Depression ; Methods ; Neuralgia ; Neuroblastoma ; Serotonin*

OBJECTIVE: The primary aim of this study was to further characterize the acute effects of amitriptyline (AMI) and escitalopram (ESC) on serum levels of ghrelin, leptin, cortisol and prolactin in healthy humans. METHODS: Eleven healthy male participants received a single dose of AMI 75 mg, ESC 10 mg, or placebo (PLA) at 9:00 PM in a double blind, randomized, controlled, repeated measures study separated by one week. Fasting morning serum levels (7:00 AM) of ghrelin, leptin, cortisol and prolactin were assessed. RESULTS: A repeated measures multivariate analysis of variance revealed a significant main effect for the factor condition (AMI, ESC, PLA). Subsequent univariate analyses demonstrated significant condition effects for ghrelin and cortisol. Post-hoc analyses demonstrated a significant reduction of ghrelin levels after AMI in comparison to PLA, and a significant reduction of cortisol levels after AMI in comparison to both ESC and PLA. Other contrasts did not reach statistical significance. CONCLUSION: Administration of a single dose of AMI, but not of ESC, leads to a significant reduction in morning serum ghrelin and cortisol levels. No effects on leptin and prolactin levels were observed. The differential impact of AMI and ESC on hormones might contribute to different adverse effect profiles of both substances.
Amitriptyline* ; Citalopram* ; Fasting ; Ghrelin ; Healthy Volunteers* ; Humans ; Hydrocortisone ; Leptin ; Male ; Multivariate Analysis ; Prolactin ; Weight Gain

PURPOSE: Headache is a common symptom during childhood. It is usually persistent and requires special care. This study aimed to identify the characteristics of headache in children < 7 years of age. METHODS: We reviewed 3 years of clinical files on children < 7 years of age with a chief complaint of headache. RESULTS: This study included 146 children (66 males, 80 females; mean age, 5.5±1.0 years). Mean symptom duration was 5.8±7.9 months. Attack durations were longer than 2 hours in 31 patients, shorter than 2 hours in 70 patients, and unchecked in 45 patients. Attack frequency was 15.1±10.6 times per month. Pain locations and characteristics were also variable. Mean pain severity score was 5.1±2.2 on the visual analog scale. Of 38 patients who underwent electroencephalography, 9 showed positive findings. Of 41 who underwent brain magnetic resonance imaging, 20 showed positive findings. The diagnoses were migraine (including probable migraine) in 34, tension-type headache in 5, and congenital malformations in 3. Medications were used in 29 patients: acetaminophen in 17, ibuprofen in 8, naproxen sodium in 1, and topiramate or amitriptyline in 3. CONCLUSION: In children aged < 7 years, headache has a relatively benign course, but detailed history taking is needed for more accurate diagnosis.
Acetaminophen ; Amitriptyline ; Brain ; Child* ; Diagnosis ; Electroencephalography ; Female ; Headache* ; Humans ; Ibuprofen ; Magnetic Resonance Imaging ; Male ; Migraine Disorders ; Naproxen ; Tension-Type Headache ; Visual Analog Scale

BACKGROUND: Current therapy for the treatment of neuropathic pain is often unsatisfactory. Considerable variation in treatment pattern still exists in spite of availability of sufficient literature from various guidelines. Recent Indian market data suggested that the utilization (sale) of drugs such as amitriptyline, pregabalin, and gabapentin was more for low-dose unit packs than that of the high-dose unit packs, raising the belief that these drugs are prescribed at a lower dose than is actually recommended in the guidelines. To test this hypothesis, a survey was conducted across speciality throughout the country to observe the prescription pattern of these drugs amongst the health care providers in India. METHODS: Three hundred fifty survey forms were distributed of which 281 forms were included for analysis. RESULTS: It was observed that the commonly used initiation and maintenance dose for amitriptyline, pregabalin, and gabapentin was 5–10 mg/day, 50–75 mg/day, and 100–300 mg/day, respectively. The reason to select the lower dosages was to have a balancing effect to achieve good efficacy with minimum side effects. Care-givers reported no side effects/not many side effects as a reason in 22.2%, 16.88%, and 23.86% patients with amitriptyline, pregabalin, and gabapentin, respectively. Sedation and giddiness were commonly reported with all three drugs. CONCLUSIONS: Commonly prescribed drugs for management of neuropathic pain, such as amitriptyline, pregabalin, and gabapentin are preferred at lower doses in Indian clinical settings. Acceptable efficacy and low tolerance to the standard dosage is believed to be the reason behind the prescribed dose.
Amitriptyline* ; Health Personnel ; Humans ; India* ; Neuralgia* ; Pregabalin* ; Prescriptions ; Surveys and Questionnaires

Neuropathic pain is usually managed pharmacologically, rather than with botulinum toxin type A (BTX-A). However, medications commonly fail to relieve pain effectively or have intolerable side effects. We present the case of a 62-year-old man diagnosed with an intracranial chondrosarcoma, which was removed surgically and treated with radiation therapy. He suffered from neuropathic pain despite combined pharmacological therapy with gabapentin, amitriptyline, tramadol, diazepam, and duloxetine because of adverse effects. BTX-A (100 units) was injected subcutaneously in the most painful area in the posterior left thigh. Immediately after the injection, his pain decreased significantly from 6/10 to 2/10 on a visual analogue scale. Pain relief lasted for 12 weeks. This case report describes intractable neuropathic pain caused by a brain tumor that was treated with subcutaneous BTX-A, which is a useful addition for the management of neuropathic pain related to a brain tumor.
Amitriptyline ; Botulinum Toxins* ; Botulinum Toxins, Type A* ; Brain Neoplasms* ; Brain* ; Chondrosarcoma ; Diazepam ; Duloxetine Hydrochloride ; Humans ; Middle Aged ; Neuralgia* ; Thigh ; Tramadol

Most dental pain is caused by an organic problem such as dental caries, periodontitis, pulpitis, or trauma. Diagnosis and treatment of these symptoms are relatively straightforward. However, patients often also complain of abnormal dental pain that has a non-dental origin, whose diagnosis is challenging. Such abnormal dental pain can be categorized on the basis of its cause as referred pain, neuromodulatory pain, and neuropathic pain. When it is difficult to diagnose a patient's dental pain, these potential alternate causes should be considered. In this clinical review, we have presented a case of referred pain from the digastric muscle (Patient 1), of pulpectomized (Patient 2), and of pulpectomized pain (Patient 3) to illustrate referred, neuromodulatory, and neuropathic pain, respectively. The Patient 1 was advised muscle stretching and gentle massage of the trigger points, as well as pain relief using a nonsteroidal anti-inflammatory and the tricyclic antidepressant amitriptyline. The pain in Patient 2 was relieved completely by the tricyclic antidepressant amitriptyline. In Patient 3, the pain was controlled using either a continuous drip infusion of adenosine triphosphate or intravenous Mg2+ and lidocaine administered every 2 weeks. In each case of abnormal dental pain, the patient's diagnostic chart was used (Fig.2 and 3). Pain was satisfactorily relieved in all cases.
Adenosine Triphosphate ; Amitriptyline ; Dental Caries ; Diagnosis* ; Humans ; Infusions, Intravenous ; Lidocaine ; Massage ; Neuralgia ; Pain, Referred ; Periodontitis ; Pulpitis ; Trigger Points

Urinary incontinence, although rarely reported, is one of the most important adverse effects of antipsychotic medication. It can be an embarrassing, distressing, and potentially treatment-limiting. Several antipsychotics, including both typical and atypical varieties, are known to induce urinary incontinence. Many antipsychotic drugs target the neural pathways controlling continence by binding to receptors of some neurotransmitters such as serotonin, dopamine, acetylcholine, and adrenaline. Pharmacological management of incontinence should be considered if there is a risk of cessation of the antipsychotic therapy or any decline in patients' compliance. Amitriptyline, desmopressin, ephedrine, and anticholinergics such as oxybutynin and trihexyphenidyl are the most frequently used agents to treat incontinence. We think that the frequency of incontinence is higher than reported in the literature, and that follow-up routines should include a form of standardized screening for all possible adverse effects, including incontinence, of any given antipsychotic. In this article, we report a case of urinary incontinence as an adverse effect of paliperidone palmitate use during maintenance therapy in a patient with schizophrenia.
Acetylcholine ; Amitriptyline ; Antipsychotic Agents ; Cholinergic Antagonists ; Compliance ; Deamino Arginine Vasopressin ; Dopamine ; Ephedrine ; Epinephrine ; Follow-Up Studies ; Humans ; Mass Screening ; Neural Pathways ; Neurotransmitter Agents ; Schizophrenia ; Serotonin ; Trihexyphenidyl ; Urinary Incontinence* ; Paliperidone Palmitate

TWIK-related K+ channel-2 (TREK-2) and TWIK-related spinal cord K+ (TRESK) channel are members of two-pore domain K+ channel family. They are well expressed and help to set the resting membrane potential in sensory neurons. Modulation of TREK-2 and TRESK channels are involved in the pathogenesis of pain, and specifi c activators of TREK-2 and TRESK may be benefi cial for the treatment of pain symptoms. However, the effect of commonly used analgesics on TREK-2 and TRESK channels are not known. Here, we investigated the effect of analgesics on TREK-2 and TRESK channels. The effects of analgesics were examined in HEK cells transfected with TREK-2 or TRESK. Amitriptyline, citalopram, escitalopram, and fluoxetine significantly inhibited TREK-2 and TRESK currents in HEK cells (p<0.05, n=10). Acetaminophen, ibuprofen, nabumetone, and bupropion inhibited TRESK, but had no effect on TREK-2. These results show that all analgesics tested in this study inhibit TRESK activity. Further study is needed to identify the mechanisms by which the analgesics modulate TREK-2 and TRESK differently.
Acetaminophen ; Amitriptyline ; Analgesics* ; Antidepressive Agents* ; Bupropion ; Citalopram ; Fluoxetine ; Humans ; Ibuprofen ; Membrane Potentials ; Potassium Channels, Tandem Pore Domain ; Sensory Receptor Cells ; Spinal Cord