Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.
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PMID:Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. 173 71

The antinociceptive effects of controlled release amitriptyline, desipramine, and placebo pellets were studied over 3 weeks using the hot plate method in 45 rats. Animals treated with desipramine at total doses of 50 mg (8 mg/kg/day) and 100 mg (16 mg/kg/day) displayed analgesia for up to 48 hours compared with the matching placebo groups. Amitriptyline did not produce significant analgesia at the same doses. By 72 hours until the final evaluation period at 21 days, the antinociceptive action of desipramine was no longer evident. These results suggest that relatively small continuously released doses of desipramine produce analgesia within 24 hours in this animal model, but an apparent analgesic tolerance develops within 3 days.
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PMID:Antinociceptive action of tricyclic antidepressant drugs in the rat. 209 40

In a randomized, double-blind crossover study, 29 patients with painful diabetic neuropathy received 6 weeks of amitriptyline and 6 weeks of an "active" placebo that mimicked amitriptyline side effects. Amitriptyline was superior to placebo in relieving pain in weeks 3 through 6. Both steady, burning pain and lancinating pains were relieved. Patients able to tolerate higher amitriptyline doses reported greater relief, through the maximum dose of 150 mg nightly. Amitriptyline analgesia was similar in depressed and nondepressed subgroups and was not associated with mood improvement. We conclude that amitriptyline relieves pain in diabetic neuropathy; this effect is independent of mood elevation.
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PMID:Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. 243 92

The post-receptorial mechanisms of the analgesic action of amitriptyline and clomipramine, two tricyclic antidepressants, were investigated in the mouse hot plate test by using an antisense strategy. Mice were injected i.c.v. with antisense oligonucleotides (aODN), complementary to the sequence of the mRNA sequence of the alpha-subunit of Gi1, Gi2 and Gi3-proteins, 18-24 h prior to the hot plate test. Treatment with aODN against Gi1alpha, Gi2alpha and Gi3alpha dose-dependently reduced the analgesia induced by both amitriptyline (15 mg/kg s.c.) and clomipramine (25 mg/kg s.c.). This antagonistic effect disappeared 7 days after the end of the i.c.v. treatment, indicating the absence of irreversible damage or toxicity. Treatment with aODN against Gi1alpha, Gi2alpha and Gi3alpha, at the active doses, did not modify the animals' pain threshold, indicating the absence of any hyperalgesic effect. Amitriptyline, clomipramine and the aODN employed, at the maximal effective doses, did not produce any alteration of motor coordination of the mice, as revealed by rotarod experiments, and spontaneous motility, as revealed by the Animex apparatus. These results indicate that amitriptyline and clomipramine induce their analgesic effect by activating all three subtypes of the Gi-proteins.
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PMID:Amitriptyline and clomipramine activate Gi-protein signaling pathway in the induction of analgesia. 1186 27

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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PMID:Peripheral interactions between dextromethorphan, ketamine and amitriptyline on formalin-evoked behaviors and paw edema in rats. 1262 Jun 9

Tricyclic antidepressants have analgesic and sedative effects in addition to their antidepressive properties. We tested the acute analgesic and locomotor inhibitory effects of the tricyclic antidepressant amitriptyline and the alpha(2)-adrenoceptor agonist clonidine in wild-type control and in alpha(2A)-adrenoceptor knockout mice in hot-plate and tail-flick tests. Amitriptyline-induced analgesia was lost in alpha(2A)-adrenoceptor knockout mice. The locomotor inhibitory effect of amitriptyline was reduced, but not fully abolished in alpha(2A)-adrenoceptor knockout mice. Similar results were obtained with clonidine. We conclude that alpha(2A)-adrenoceptors appear to have a significant role in amitriptyline-induced acute analgesia in mice, and that alpha(2A)-adrenoceptors also participate in the sedative effects of amitriptyline.
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PMID:Loss of amitriptyline analgesia in alpha 2A-adrenoceptor deficient mice. 1475 40

In this study, we aimed to reveal the interaction between the tricyclic antidepressant amitriptyline and a1-adrenoceptor antagonist prazosin in mice by using an analgesiometric device hot-plate. Amitriptyline (10 mg/kg) has analgesic effect as expected. Neither of the prazosin doses (0.1, 0.2, 0.5, 1 mg/kg) displayed analgesic effect alone. The combination of lower doses of prazosin (0.1, 0.2, 0.5 mg/kg) with amitriptyline (10 mg/kg) potentiated the antinociceptive effect of this drug. However, the relatively higher dose of prazosin (1 mg/kg) did not effect amitriptyline analgesia. Thus we conclude that the antinociceptive effect of amitriptyline is potentiated by low doses of prazosin.
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PMID:[Low doses of prazosin potantiates the antinociceptive/analgesic effect of amitriptyline]. 1579 2

There is a legal requirement to provide analgesia for velvet antler removal in New Zealand. Currently, this is achieved using local anaesthetic blockade, with or without systemically administered sedative/analgesic agents, or by compression in 1-year-old stags. Lignocaine hydrochloride 2% is most commonly used and is most effective when administered as a high-dose ring block. Combinations of various amino-amide local anaesthetic agents can achieve rapid onset and prolonged duration of analgesia, though concerns about drug residues and carcinogenic potential of a lignocaine metabolite have led to consideration of the amino-ester family of local anaesthetics as alternatives. Systemically administered analgesics, including opioids, alpha-2-adrenergic agents and ketamine provide dose-dependent sedation and analgesia. However, none are sufficient, alone or in combination, to produce surgical analgesia at currently recommended dose rates and when reversal agents are given, analgesic effects are usually reversed as well as sedation. Thus, local anaesthetic blockade is still indicated, though the potential for drug or drug-metabolite residues in velvet antler remains a concern. The need for and effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for post-operative analgesia requires investigation. Amitriptyline, locally administered opioid agonists, tramadol and other systemically administered agents may warrant future investigation for surgical and post-operative analgesia for velvet antler removal.
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PMID:Chemical analgesia for velvet antler removal in deer. 1603 79

Opioids have been discovered to have Toll-like receptor (TLR) activity, beyond actions at classical opioid receptors. This raises the question whether other pharmacotherapies for pain control may also possess TLR activity, contributing to or opposing their clinical effects. We document that tricyclics can alter TLR4 and TLR2 signaling. In silico simulations revealed that several tricyclics docked to the same binding pocket on the TLR accessory protein, myeloid differentiation protein 2 (MD-2), as do opioids. Eight tricyclics were tested for effects on TLR4 signaling in HEK293 cells over-expressing human TLR4. Six exhibited mild (desipramine), moderate (mianserin, cyclobenzaprine, imiprimine, ketotifen) or strong (amitriptyline) TLR4 inhibition, and no TLR4 activation. In contrast, carbamazepine and oxcarbazepine exhibited mild and strong TLR4 activation, respectively, and no TLR4 inhibition. Amitriptyline but not carbamazepine also significantly inhibited TLR2 signaling in a comparable cell line. Live imaging of TLR4 activation in RAW264.7 cells and TLR4-dependent interleukin-1 release from BV-2 microglia revealed that amitriptyline blocked TLR4 signaling. Lastly, tricyclics with no (carbamazepine), moderate (cyclobenzeprine), and strong (amitriptyline) TLR4 inhibition were tested intrathecally (rats) and amitriptyline tested systemically in wildtype and knockout mice (TLR4 or MyD88). While tricyclics had no effect on basal pain responsivity, they potentiated morphine analgesia in rank-order with their potency as TLR4 inhibitors. This occurred in a TLR4/MyD88-dependent manner as no potentiation of morphine analgesia by amitriptyline occurred in these knockout mice. This suggests that TLR2 and TLR4 inhibition, possibly by interactions with MD2, contributes to effects of tricyclics in vivo. These studies provide converging lines of evidence that several tricyclics or their active metabolites may exert their biological actions, in part, via modulation of TLR4 and TLR2 signaling and suggest that inhibition of TLR4 and TLR2 signaling may potentially contribute to the efficacy of tricyclics in treating chronic pain and enhancing the analgesic efficacy of opioids.
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PMID:Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. 2038 91

Norepinephrine and serotonin involvement in nociceptive functions is supported by observations of analgesic effects of norepinephrine transporter (NET) and serotonin transporter (SERT) inhibitors such as amitriptyline. However, the relative contribution of NET and SERT to baseline nociception, as well as amitriptyline analgesia, is unclear. Amitriptyline and morphine analgesia in wild-type (WT) mice and littermates with gene knockout (KO) of SERT, NET or both transporters was conducted using the hotplate and tail-flick tests. Hypoalgesia was observed in NET KO mice, and to a lesser extent in SERT KO mice. The magnitude of this hypoalgesia in NET KO mice was so profound that it limited the assessment of drug-induced analgesia. Nonetheless, the necessary exclusion of these subjects because of profound baseline hypoalgesia strongly supports the role of norepinephrine and NET in basal nociceptive behavior while indicating a much smaller role for serotonin and SERT. To further clarify the role of NET and SERT in basal nociceptive sensitivity further experiments were conducted in SERT KO and NET KO mice across a range of temperatures. NET KO mice were again found to have pronounced thermal hypoalgesia compared to WT mice in both the hotplate and tail-flick tests, while only limited effects were observed in SERT KO mice. Furthermore, in the acetic acid writhing test of visceral nociception pronounced hypoalgesia was again found in NET KO mice, but no change in SERT KO mice. As some of these effects may have resulted from developmental consequences of NET KO, the effects of the selective NET blocker nisoxetine and the selective SERT blocker fluoxetine were also examined in WT mice: only nisoxetine produced analgesia in these mice. Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT in mice.
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PMID:A greater role for the norepinephrine transporter than the serotonin transporter in murine nociception. 2112 46


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