Administration Of Amitriptyline Research Articles

Amitriptyline enhances extracellular tissue levels of adenosine in the rat hindpaw and inhibits adenosine uptake

Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; this is reduced by adenosine receptor antagonists and appears to involve endogenous adenosine. The present study used peripheral microdialysis: (a) to determine whether amitriptyline could enhance extracellular tissue levels of endogenous adenosine in the rat hindpaw and (b) to examine mechanisms by which such an increase could occur. Local injection of amitriptyline into the plantar hindpaw, at doses that produce peripheral antinociception (100–300 nmol), produced an increase in local extracellular levels of adenosine. When injected in combination with formalin, which also enhances such levels of adenosine, an additive increase was observed. This adenosine originated partly as nucleotide, as inhibition of ecto-5′-nucleotidase reduced the amount of adenosine detected in the probe following administration of amitriptyline. When administered in combination with exogenous adenosine, amitriptyline augmented recovery of adenosine in the probe. Pretreatment of rats with capsaicin augmented the ability of amitriptyline to increase adenosine levels detected in the dialysis probe; it also enhanced tissue recovery of exogenously administered adenosine. In uptake studies using cultured rat C6 glioma cells, amitriptyline inhibited adenosine uptake by an adenosine transporter (IC50 0.37±0.12 mM). In enzyme assays, amitriptyline had no effect on adenosine kinase or adenosine deaminase activity. These results demonstrate that amitriptyline: (a) enhances extracellular tissue levels of adenosine in the rat hindpaw following local administration in vivo and (b) inhibits adenosine uptake but has no effect on metabolism in vitro. Therefore, increased extracellular adenosine levels in vivo appear to result partially from extracellular conversion of nucleotide and partially from inhibition of uptake.

Chronic administration of venlafaxine fails to attenuate 5-HT1A receptor function at the level of receptor-G protein interaction

In this study venlafaxine was administered to rats at a low, moderate or high dose; for comparison, the selective serotonin reuptake inhibitor (SSRI) sertraline and the tricyclic antidepressant (TCA) amitriptyline were also included. We evaluated, using quantitative autoradiography, the effect of these antidepressant treatments on [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT, a measure of the capacity of 5-HT1A receptors to activate G proteins. Chronic administration of amitriptyline resulted in a marked increase in 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the hippocampus which was accompanied by an increase in 5-HT1A receptor number. 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the hippocampus was also increased by chronic treatment with the highest dose of venlafaxine; 5-HT1A receptor number, however, was not significantly altered. In serotonergic cell body areas (i.e. dorsal and median raphe nuclei), 5-HT1A receptor-stimulated [35S]GTPgammaS binding was not altered by chronic administration of amitriptyline, sertraline or venlafaxine. Chronic TCA treatment does not desensitize somatodendritic 5-HT1A autoreceptor function. However, the lack of effect of chronic sertraline treatment on 5-HT1A receptor-stimulated [35S]GTPgammaS binding is in contrast to what has been observed previously following chronic administration of the SSRI fluoxetine, and suggests that different SSRIs may regulate somatodendritic 5-HT1A autoreceptor function differently depending on their pharmacology. Our data also suggest that the desensitization of somatodendritic 5-HT1A autoreceptors observed in electrophysiological studies following chronic venlafaxine administration is not at the level of receptor-G protein interaction. The hypothermic response in vivo to acute injection of 8-OH-DPAT was significantly attenuated following chronic treatment with venlafaxine or sertraline, but not amitriptyline.

Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain

The effects of acute, systemic administration of amitriptyline, duloxetine and mirtazapine (antidepressant drugs that variously affect extracellular noradrenaline and serotonin levels) and the selective serotonin reuptake inhibitor (SSRI) citalopram were compared in rat models of experimental pain. None of the drugs (all 3–30 mg/kg, i.p.) affected acute nociceptive responses as measured in the tail flick test. In the hot plate test, duloxetine and mirtazapine significantly increased ( P<0.05) the nociceptive response latency, whereas amitriptyline and citalopram were ineffective. In the formalin test, duloxetine and citalopram significantly attenuated, whereas amitriptyline and mirtazapine increased, second phase flinching behaviour (all P<0.05). However, amitriptyline and mirtazapine reduced second phase licking behaviour. In the chronic constriction injury model of neuropathic pain, thermal hyperalgesia of the injured hindpaw was significantly attenuated by all four drugs ( P<0.05); only amitriptyline and duloxetine fully reversed thermal hypersensitivity. None of the drugs tested attenuated mechanical allodynia. In contrast amitriptyline, duloxetine and mirtazapine significantly reduced mechanical hyperalgesia ( P<0.05); citalopram was ineffective. No drug-related effects on motor performance in the rotarod test were observed. These results (a) highlight the difficulty in correlating antinociceptive effects of drugs from different antidepressant classes across a range of animal pain models and (b) suggest that antidepressants that variously affect both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs (as exemplified by citalopram), against a range of pain-like behaviours in an animal model of neuropathic pain.

A case of complex regional pain syndrome type II after transradial coronary intervention

The transradial approach for coronary catheterization is now a routine technique without serious complications at the puncture site. We report a case of complex regional pain syndrome type II (CRPS type II) in the hand after the transradial coronary intervention, which may alert medical personnel that the technique may cause serious regional pain with disability. A 61-year-old woman underwent coronary intervention via the right radial artery for the treatment of unstable angina. After the operation she complained of severe pain in the right hand, consistently felt along the median nerve distribution. The nerve conduction study suggested carpal tunnel syndrome. We made a diagnosis of CRPS type II, and the patient received stellate ganglion blockade, cervical epidural blockade, and administration of amitriptyline and loxoprofen. The symptoms gradually improved and her activities of daily living markedly improved. The median nerve appeared to be damaged by local compression and potential ischemia. Careful attention should be paid to avoid CRPS type II, associated with excess compression.

Neurologic and histopathologic evaluation after high-volume intrathecal amitriptyline

Accumulating evidence indicates that amitriptyline decreases pain sensation when administered orally, intraperitoneally, or for sciatic nerve block. Previous reports of intrathecal administration of amitriptyline have yielded inconsistent results. The failure of amitriptyline to provide antinociception may partly be related to its high logP (octanol-water partition coefficient) and consequent poor spread within the cerebrospinal fluid. We evaluated spinal block after various concentrations of amitriptyline administered intrathecally in a fixed high volume. We administered 100 microL of 5, 10, 15.9 (0.5%), 25, 50, or 100 mmol/L amitriptyline hydrochloride solution or 100 microL of 15.4 mmol/L (0.5%) bupivacaine hydrochloride solution intrathecally to rats. The neurologic deficit was evaluated by antinociceptive, motor, and proprioceptive responses, and the spinal cord was examined for histopathologic changes. Doses of 100 microL amitriptyline at 15.9 mmol/L (0.5%) and 25 mmol/L produced longer complete nerve block than did bupivacaine at 15.4 mmol/L (0.5%); 5 and 10 mmol/L amitriptyline produced only partial nerve block. However, with 100 microL intrathecal amitriptyline at 50 and 100 mmol/L, many rats did not fully recover from spinal block. Severe axonal degeneration, myelin breakdown, and replacement of neuronal structures by vacuoles were seen in the spinal root section of animals injected with concentrations higher than 25 mmol/L amitriptyline. At lower doses, intrathecal injection of high volumes of amitriptyline results in long-acting spinal block. At higher doses, intrathecal amitriptyline results in irreversible neurologic deficit. Therefore, we do not recommend the use of intrathecal amitriptyline because of a very low therapeutic index.

Amitriptyline administration transforms tumor necrosis factor-alpha regulation of norepinephrine release in the brain

The present study demonstrates that the mixed action antidepressant drug amitriptyline enhances norepinephrine (NE) release by transforming the nature of the response of neurons to both tumor necrosis factor-alpha (TNF) as well as to an alpha(2)-adrenergic agonist in an area of the central nervous system (CNS) rich in adrenergic neurons. Administration of the antidepressant drug amitriptyline for 1 day or 14 days to rats significantly increases TNF bioactivity in total homogenates of the locus coeruleus (LC) and the hippocampus as assessed by the WEHI-13VAR bioassay. Superfusion and electrical field stimulation of rat hippocampal brain slices were used to study the regulation of NE release. Exposure to TNF, as well as activation of the alpha(2)-adrenergic autoreceptor inhibits stimulation-evoked norepinephrine (NE) release from adrenergic neurons of the CNS from naïve rats. Superfusion of hippocampal slices isolated from rats chronically (14 days) administered amitriptyline demonstrates that TNF inhibition of NE release is transformed, such that TNF facilitates NE release, dependent upon alpha(2)-adrenergic activation. Furthermore, chronic administration of amitriptyline increases stimulation-evoked NE release and decreases alpha(2)-adrenergic autoreceptor inhibition of NE release, an effect not observed with acute drug administration. These data support the hypothesis that chronic antidepressant drug administration, through regulation of TNF expression, transforms alpha(2)-adrenergic receptors such that they function to facilitate NE release, suggesting a mechanism of action of antidepressant drugs.

Primary afferents: Antidepressants enhance extracellular levels of adenosine in the rat hindpaw and inhibit adenosine uptake

Peripheral antinociception by amitritpyline is inhibited by methylxanthine adenosine receptor antagonists suggesting involvement of endogenous adenosine in its action. This study examined the effects of antidepressants on in vivo extracellular levels of endogenous adenosine in the rat hindpaw, explored the mechanism of the increase, and determined in vitro effects of antidepressants on adenosine transport and enzymes involved in metabolism. Peripheral microdialysis of the hindpaw was used to determine extracellular tissue levels of adenosine. Adenosine uptake was determined using rat C6 glioma cells (contain rENT, transfected with DNA for rENT1); effects on enzymes were determined using standard assays. Amitriptyline (100-1000 nmol), injected locally into the rat hindpaw, enhances extracellular tissue levels of adenosine and augments release of adenosine by 1.5% formalin. Desipramine and fluoxetine produce similar effects. For amitriptyline, the adenosine originates from nucleotide, as inhibition of ecto-5'-nucleotidase (with α,β-methylene-ADP) inhibits the appearance of adenosine following exogenous administration of AMP and amitriptyline. Amitriptyline also greatly enhances the in vivo tissue recovery of adenosine when co-injected with exogenous adenosine. In uptake studies, all three antidepressants inhibit transport by rENT1 and rENT2 (>80% inhibition, IC50 0.24-1.02 mM). In enzyme assays for adenosine kinase and adenosine deaminase activity, minimal effects are observed. Antidepressants enhance extracellular tissue levels of adenosine in the rat hindpaw following local administration. For amitriptyline, the adenosine originates as nucleotide which is then converted to adenosine; it further involves inhibition of adenosine uptake from the extracellular space. This adenosine contributes to peripheral antinociception observed in behavioral studies. Supported by CIHR.

Effects of the suppression of acute herpetic pain by gabapentin and amitriptyline on the incidence of delayed postherpetic pain in mice

The inoculation of mice with herpes simplex virus type-1 (HSV-1) causes herpes zoster-like skin lesions and pain-related responses (tactile allodynia and mechanical hyperalgesia) from day 5 after inoculation. Skin lesions completely heal by day 15 after inoculation, but about half of mice with acute herpetic pain show pain-related responses long after the lesions heal. Using this mouse model, we examined the effects of repeated administration of gabapentin and amitriptyline on the acute herpetic pain and the incidence of postherpetic pain. Gabapentin and amitriptyline were administered three times daily from day 5 to 11 after inoculation. Postherpetic pain-related responses were assessed on day 30 after inoculation. Gabapentin (10–100 mg/kg) produced the dose-dependent inhibition of acute herpetic pain-related responses. This medication produced marked reduction in the incidence of delayed postherpetic pain and the dose of 100 mg/kg produced the complete inhibition. Amitriptyline (10 mg/kg) did not affect the acute pain-related responses in the initial 3- and 2-day periods and then gradually inhibited them. This dosage produced a substantial but non-significant decrease in the incidence of postherpetic pain-related responses. Amitriptyline (1 and 3 mg/kg) was without effects on acute herpetic and postherpetic pain-related responses. The results strongly support the idea that the severity of the acute herpetic pain is a risk factor of postherpetic neuralgia. It may be worth testing the effects of gabapentin on acute herpetic pain and the incidence of postherpetic neuralgia in human subjects.

Amitriptyline eliminates calculi through urinary tract smooth muscle relaxation

We investigated the effects of amitriptyline in the urinary tract smooth muscle and urolithiasis. Cats presenting with obstructive acute renal failure (ARF) received amitriptyline, and renal function and survival rates were analyzed. Isometric contractions and membrane potentials of rat, pig, or human isolated urinary tract smooth muscle were recorded in the presence or absence of amitriptyline. Twenty cats with obstructive ARF caused by urethral plugs received amitriptyline. In all cases, plugs were completely eliminated, and renal function returned to normal, with a 100% survival rate in the follow-up. Amitriptyline produced potent relaxations in rat urethral strips, accompanied by significant reductions in urethral ring membrane potential. This effect was prevented by pretreatment of urethral rings with 4-aminopyridine (4-AP), a voltage-dependent potassium channel blocker. Amitriptyline abolished in a reversible manner acetylcholine-, bradykinin-, and KCl-induced contractions in rat isolated bladder, and this effect was also prevented by 4-AP. Of interest, spontaneous and KCl-induced contractions of pig and human isolated ureter were also blocked by amitriptyline. Our results indicate that amitriptyline is an effective and potent relaxant of urinary tract smooth muscle and this effect is mediated by opening of voltage dependent-potassium channels. We suggest that amitriptyline administration may help to promote elimination of urinary calculi.

Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat.

In this study, we examined antihyperalgesic and analgesic actions after local peripheral administration of ketamine and amitriptyline in a rat model of mild thermal injury. Exposure of the hindpaw to 52 degrees C for 45 s under anesthesia produced a subsequent thermal hyperalgesia lasting at least 2 h. The local peripheral administration of ketamine (100-1000 nmol) 15 min before the thermal injury produced an antihyperalgesic effect when injected into the ipsilateral paw, whereas amitriptyline produced both antihyperalgesic (300 nmol) and analgesic (1000 nmol) effects. Administered after the thermal injury, ketamine had no effect, whereas amitriptyline retained its analgesic but not its antihyperalgesic effect. Amitriptyline (300 and 1000 nmol) produced an analgesic action when administered into the normal nonsensitized hindpaw. Both drugs increase paw volume, particularly at larger doses; biogenic amines are not involved in the action of amitriptyline, as was shown previously for ketamine. These results indicate that (a) ketamine produces antihyperalgesia, but not analgesia, when administered locally with a mild thermal injury model; (b) amitriptyline produces both antihyperalgesia and analgesia when administered locally; and (c) the increase in paw volume produced by these drugs occurs by different mechanisms. This study examines the pain-relieving properties of the local peripheral administration of ketamine and amitriptyline, two drugs in current clinical use, in a thermal injury model of hyperalgesia and demonstrates both antihyperalgesic and analgesic properties. These observations provide support for their potential use as local (e.g., topical) analgesics.

Dynamic changes in AP-1 transcription factor DNA binding activity in rat brain following administration of antidepressant amitriptyline and brain-derived neurotrophic factor

The present study was undertaken to examine the effects of the antidepressant, amitriptyline, and brain-derived neurotrophic factor (BDNF) on activator protein-1 (AP-1) DNA binding activity in the rat brain. Acute administration of amitriptyline (5 or 10 mg/kg) initially increased but then decreased AP-1 DNA binding activity in the rat frontal cortex and hippocampus. Chronic administration of amitriptyline (5 or 10 mg/kg, once daily for 3 weeks) initially decreased AP-1 DNA binding activity but ultimately resulted in its persistent elevation in the rat frontal cortex. In contrast, the chronic administration of amitriptyline did not affect the low activity of AP-1 DNA binding in the hippocampus. However, chronic administration of amitriptyline (10 mg/kg, once daily for 3 weeks) significantly increased BDNF protein levels in the hippocampus (by 26.9%) and frontal cortex (by 24.6%). Direct infusion of BDNF (1 μg) into the hippocampal dentate gyrus significantly increased hippocampal AP-1 DNA binding activity. These results suggest that AP-1 transcription factor may be modulated by BDNF and that it may be an important target for the action of antidepressants.

Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.

It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field.

Effects of acute amitriptyline administration on memory, anxiety and activity in male and female mice

AbstractThe effects of acute administration of amitriptyline on memory consolidation in male and female CD1 mice were investigated. Three doses of this tricyclic antidepressant (7.5, 15 and 30 mg/kg) were administered immediately after inhibitory avoidance training. Forty‐five minutes after injection, subjects explored the elevated plus‐maze for five minutes. Subjects were tested for avoidance twenty‐four hours later. Amitriptyline impaired inhibitory avoidance consolidation at doses 7.5, 15 and 30 mg/kg in males, and at doses 7.5 and 30 mg/kg in females. In the elevated plus‐maze, amitriptyline had no effect on anxiety (percentage of open arm entries) and induced a dose‐dependent impairment of activity (number of closed arm entries). The observed sex differences were limited to subtle stronger effects of amitriptyline in males than in females on inhibitory avoidance. These results indicate that acute amitriptyline administration produces retrograde amnesia on inhibitory avoidance, which does not seem be mediated by anxiolytic effects.

Role of Gi Proteins in the Antidepressant-like Effect of Amitriptyline and Clomipramine

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotides directed against the α subunit of different Gi-proteins (anti-Giα1, anti-Giα2, anti-Giα3, anti-Goα1, anti-Goα2) 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 μg per mouse i.c.v.), administered 11 days before the mouse forced swimming test. Anti-Giα1 (12.5 μg per mouse i.c.v.), anti-Giα2 (12.5 μg per mouse i.c.v.), anti-Giα3 (6.25 μg per mouse i.c.v.), and anti-Goα1 (6.25 μg 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-Goα2 (1.56-12.5 μg 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 Gi1, Gi2, Gi3, and Go1 protein subtypes and the lack of involvement by Go2 protein subtype in the transduction mechanism responsible for the antidepressant-like effect produced by amitriptyline and clomipramine.

Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats

Recent observations suggest the involvement of adenosine in the peripheral antinociceptive effect of amitriptyline in nerve-injury-induced neuropathic pain. The aim of the present investigation was to evaluate, firstly, the peripheral and systemic effects of amitriptyline on tactile allodynia in the streptozotocin (STZ)-induced diabetic rat model of neuropathic pain and, secondly, whether caffeine coadministration affects the actions of amitriptyline. Diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (50 mg/kg), and tactile allodynia was detected by application of von Frey filaments to the ventral surface of the hindpaw. Both systemic (0.5–2.0 mg/kg, i.p.) and peripheral (10–100 nmol, subcutaneously (s.c.)) administration of amitriptyline were found to produce increases in paw withdrawal thresholds, at higher doses. Coadministration of caffeine (5 mg/kg, i.p.; 1500 nmol, s.c.), at doses which produced no effect on its own, partially reversed systemic and local anti-allodynic effects of amitriptyline. These results indicate an anti-allodynic effect of both peripheral and systemic amitriptyline, and suggest the involvement of endogenous adenosine in the action of amitriptyline in this rat model of painful diabetic neuropathy. These data also suggest that topical application of tricyclic antidepressants may be useful in treating neuropathic pain in diabetics.

Treatments for chronic pain associated with spinal cord injuries: many are tried, few are helpful.

The objective was to investigate, in two community samples of people with spinal cord injuries, the frequency of use of different pain treatments and the perceived helpfulness of these treatments. A postal survey was conducted in the community. The participants were 471 persons aged 18 years or older who had spinal cord injuries and pain. There were 2 separate samples (n = 308 and n = 163). The pain treatments used, the helpfulness of these treatments, and the Chronic Pain Grade questionnaire answers were assessed. Respondents reported multiple pain treatments (range of 0-14 and median of 4 in sample 1; range of 0-16 and median of 4 in sample 2). The most commonly reported treatments were oral medications and physical therapy. Medication types most commonly reported were nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. The treatments rated as most helpful were opioid medications, physical therapy, and diazepam therapy, and those rated as least helpful were spinal cord stimulation, counseling or psychotherapy, administration of acetaminophen, and administration of amitriptyline. Alternative treatments reported as most helpful were massage therapy and use of marijuana. Acupuncture was tried by many but was rated as only moderately helpful. This survey of two large samples of community-dwelling individuals with spinal cord injury-related chronic pain indicates that multiple pain treatments are tried but only a few are rated as more than somewhat helpful. Furthermore, the treatments that are most commonly reported are not always those that are rated as most helpful. The findings point to a number of potentially fruitful directions for future research.

Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression

A high incidence of depression is found in subjects with Alzheimer's disease (AD), in whom many antidepressants are contraindicated because they have anticholinergic activity. We have designed a new cholinesterase inhibitor TV3326 [( N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] for the treatment of AD, which has neuroprotective activities and also blocks monoamine oxidase (MAO) A and B in the brain but not in the intestine after chronic administration. To examine the antidepressant and anxiolytic potential of TV3326 in rats and compare them with those of its R isomer TV3279, which lacks MAO-inhibitory activity, and of amitriptyline and moclobemide. Each of the drugs was administered orally, acutely or once daily for 2 weeks, and its effect was evaluated on the behavior of rats in the forced swim test (FST) and plus maze (EPM) test. Immobility in the FST was reduced by 56% after acute and chronic administration of amitriptyline (10 mg/kg) and by 42% after acute administration of moclobemide (20 mg/kg) and by 63% when this drug was given chronically. TV3326 (26 mg/kg) only reduced immobility (by 44%) when given chronically and inhibited brain MAO-A and -B by more than 66%. TV3279 had no significant effect in the FST. All the drugs except TV3326 increased anxiogenic activity in rats in EPM, as indicated by a more than 50% decrease in the time in open arms after chronic administration. TV3326 has potential antidepressant-like activity when given in a dose regimen that causes significant inhibition of brain MAO-A and -B. Together with its neuroprotective properties, this action could make TV3326 a potentially valuable drug for the treatment of dementia in patients with depression.

Management of fibromyalgia: what are the best treatment choices?

Fibromyalgia still represents an enigma to modern medicine and the aetiopathogenesis is far from explored. The management of patients with fibromyalgia is thus mostly based on empirical research, and only a few controlled studies have been performed. Basic drug therapy rests on the administration of amitriptyline and conventional analgesics. Such therapy should be initiated only after careful patient information and delineation of therapeutic goals are provided. Any drug therapy should be administered in combination with physical treatment and cognitive behavioural therapy. Because of the appearing contours of pathogenic mechanisms, hopefully a number of new drugs will be available to the patients with this complex pain syndrome in the near future.

Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions

This study was designed to determine (1) whether chronic amitriptyline administration was effective in alleviating symptoms of neuropathic pain in a rat model of spinal nerve injury, and (2) whether the effect of amitriptyline involved manipulation of endogenous adenosine, by determining the effect of caffeine, a non-selective adenosine A 1 and A 2 receptor antagonist, on its actions. Nerve injury was produced by unilateral spinal nerve ligation of the fifth and sixth lumbar nerves distal to the dorsal root ganglion, and this resulted in stimulus-evoked thermal hyperalgesia and static tactile mechanical allodynia. Animals received pre- and post-surgical intraperitoneal doses of amitriptyline (10 mg/kg) and caffeine (7.5 mg/kg), alone or in combination, and following surgery, were administered amitriptyline (15–18 mg/kg/day) and caffeine (6–8 mg/kg/day), alone or in combination, in the drinking water. Rats were tested for thermal reaction latencies and static tactile thresholds at 7, 14 and 21 days following surgery. In the paw ipsilateral to the nerve ligation, chronic amitriptyline administration consistently decreased the thermal hyperalgesia produced by spinal nerve ligation over a 3-week period, and this effect was blocked by concomitant caffeine administration at all time intervals. In the contralateral paw, thermal withdrawal latencies were more variable, with the most reproducible finding being a reduction in thermal thresholds in the amitriptyline–caffeine combination group. There was no effect by either drug or the drug combination on the static tactile allodynia produced by spinal nerve ligation in the ipsilateral paw. However, chronic amitriptyline administration induced a tactile hyperaesthesia in the contralateral paw at all time intervals, and this effect was exacerbated by concomitant chronic caffeine administration. The results of this study indicate that chronic administration of amitriptyline is effective in alleviating thermal hyperalgesia, but not static tactile allodynia, in the hindpaw ipsilateral to nerve injury, and the block of this effect by caffeine suggests that this effect is partially achieved through manipulation of endogenous adenosine systems. Additionally, chronic amitriptyline administration induces contralateral hyperaesthetic responses that are augmented by caffeine. Both the symptom-specific effect, and adenosine involvement in amitriptyline action may be important considerations governing its use in neuropathic pain.

Antinociception by tricyclic antidepressants in the rat formalin test: differential effects on different behaviours following systemic and spinal administration

The present study (1) examined analgesic effects of systemically and spinally administered antidepressants (ADs) on phase 2 flinching and biting/licking behaviours in the rat formalin test, a model considered to be of greater relevance to clinical pain than acute threshold tests, and (2) determined whether motor or anti-inflammatory effects contributed to such actions. Systemic administration of amitriptyline (3–20 mg/kg) produced a dose-related enhancement of flinching behaviours, while at the same time suppressing biting/licking behaviours. Imipramine (except for 20 mg/kg), nortriptyline, desipramine and fluoxetine had no significant effect on flinching behaviours, while producing a dose-related suppression of biting/licking behaviours. When administered spinally, either by acute lumbar puncture or via chronically implanted intrathecal cannulas, amitriptyline similarly augmented flinching behaviours. When given by lumbar puncture, amitriptyline suppressed biting/licking behaviours, but when intrathecal cannulas were used, this behaviour was not expressed in the formalin group. Other ADs also suppressed biting/licking behaviours without affecting flinching when given by lumbar puncture. Effects on paw volume were determined at the end of behavioural testing. Systemic administration of all ADs produced a dose-related reduction in paw volume. Spinal administration of nortriptyline by lumbar puncture also reduced paw volume, but for other agents, the reduction was not significant. Motor effects were noted qualitatively throughout these experiments, and considered in relation to nociceptive behaviours. These results indicate (a) a marked dissociation between the effects of systemic ADs on flinching and biting/licking behaviours in the formalin test, (b) spinal efficacy of ADs that essentially reproduces effects seen with systemic administration when given by lumbar puncture, (c) a lack of causality between anti-inflammatory effects of ADs and their analgesic properties in the formalin test, and (d) a contribution of motor effects to analgesic actions at higher doses affecting biting/licking but not flinching behaviours.