Amitriptyline potentiates morphine analgesia by direct action on the central nervous system

The Ohio State University, Columbus, Ohio, United States
Annals of Neurology (Impact Factor: 9.98). 02/1983; 13(2):160-4. DOI: 10.1002/ana.410130209
Source: PubMed


Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.

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    • "Tricyclic antidepressants (TCAs) are a class of medications that have been indicated for chronic pain, fibromyalgia, and neuropathic pain [33, 34]. Their pain mitigating effects are not clear, but it is postulated that TCAs work on central serotonergic and noradrenergic signals, which affect central pain pathways [35]. Although their use is widespread, there are limited studies specifically for the treatment of MPS. "
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    ABSTRACT: Myofascial pain syndrome (MPS) is defined as pain that originates from myofascial trigger points in skeletal muscle. It is prevalent in regional musculoskeletal pain syndromes, either alone or in combination with other pain generators. The appropriate evaluation and management of myofascial pain is an important part of musculoskeletal rehabilitation, and regional axial and limb pain syndromes. This article reviews the current hypotheses regarding the treatment modalities for myofascial trigger points and muscle pain. Through a critical evidence-based review of the pharmacologic and nonpharmacologic treatments, the authors aim to provide clinicians with a more comprehensive knowledge of the interventions for myofascial pain.
    Full-text · Article · Jun 2013
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    • "The central pain theory that explains the mechanisms of antidepressants that are involved in the inhibition of pain perception appears to be distinct from their antidepressant action, based on the observation that lower doses are effective in alleviating symptoms of chronic pain [1]. Inhibition of monoamine reuptake in the central nervous system [56], as well as activation of the opioid system [9] [59], has been offered as a possible mechanism mediating antidepressant analgesia/antinociception. However, the finding that the phosphodiesterase inhibitor (rolipram) that is both an analgesic as well as an antidepressant does not directly affect neurotransmitter reuptake or the opioid system, but does suppress TNF production [32] [33] [67], supports the hypothesis that neuromodulators/neurotrophic factors mediate the antinociceptive action of antidepressants [39]. "
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    ABSTRACT: The manifestation of chronic, neuropathic pain includes elevated levels of the cytokine tumor necrosis factor-alpha (TNF). Previously, we have shown that the hippocampus, an area of the brain most notable for its role in learning and memory formation, plays a fundamental role in pain sensation. Using an animal model of peripheral neuropathic pain, we have demonstrated that intracerebroventricular infusion of a TNF antibody adjacent to the hippocampus completely alleviated pain. Furthermore, intracerebroventricular infusion of rTNF adjacent to the hippocampus induced pain behavior in naïve animals similar to that expressed during a model of neuropathic pain. These data support our premise that enhanced production of hippocampal-TNF is integral in pain sensation. In the present study, TNF gene expression was induced exclusively in the hippocampus, eliciting increased local bioactive TNF levels, and animals were assessed for pain behaviors. Male Sprague-Dawley rats received stereotaxic injection of gold nanorod (GNR)-complexed cDNA (control or TNF) plasmids (nanoplasmidexes), and pain responses (i.e., thermal hyperalgesia and mechanical allodynia) were measured. Animals receiving hippocampal microinjection of TNF nanoplasmidexes developed thermal hyperalgesia bilaterally. Sensitivity to mechanical stimulation also developed bilaterally in the rat hind paws. In support of these behavioral findings, immunoreactive staining for TNF, bioactive levels of TNF, and levels of TNF mRNA per polymerase chain reaction analysis were assessed in several brain regions and found to be increased only in the hippocampus. These findings indicate that the specific elevation of TNF in the hippocampus is not a consequence of pain, but in fact induces these behaviors/symptoms.
    Full-text · Article · Jul 2012 · Pain
    • "This suggests a complex mechanism underlying the antinociceptive effect of antidepressants. Opioids reduce the sensory discriminative component of pain[28] and antidepressant produce analgesia by potentiating the pain modulating system rather than having a direct synaptic effect.[29] Opiates enhance serotonergic activity in the brain by increasing the turnover rate of serotonin, without altering overall concentration of neurotransmitter,[30] through an indirect action via inhibition of gamma-amino-butyric acid (GABA)- containing neurons in the dorsal raphe nuclei and also by increasing 5-HT turnover at the spinal cord level.[31] "
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    ABSTRACT: Earlier studies have demonstrated that Bacopa monniera (BM), a plant described in Ayurveda for many CNS actions was found to exhibit antidepressant (methanolic extract at 20mg/kg and 40mg/kg p.o.) as well as antinociceptive activity (aqueous extract (AE) at 80 mg/kg, 120 mg/kg and 160 mg/kg p.o.). The present study sought to explore the possible mechanisms of antinociceptive effects of aqueous extract of Bacopa monniera (AEBM) at 80 mg/kg, 120 mg/kg and 160 mg/kg given orally. AEBM was given singly as well as with selective α2 receptor blocker Yohimbine, selective β1 receptor blocker Atenolol, serotonin receptor antagonist Cyproheptadine and a non-selective opioid receptor antagonist naloxone in experimental groups of mice and rats under strict protocols and conditions. We observed that the antinociceptive effects of AEBM in the acetic acid writhing test was prevented by prior treatment with the selective Yohimbine (1 mg/kg, i.p; 14.50 ± 2.26 and 37.17 ± 2.14 writhes in the AEBM-treated and yohimbine pre-treated AEBM groups, respectively) and selective β1 Atenolol receptor blocker (1 mg/kg, i.p; 14.50 ± 2.26 and 31.00 ± 5.44 writhes in the AEBM-treated and yohimbine pre-treated AEBM groups, respectively). In the formalin test, the reduction in licking time with AEBM was found to be reversed by prior treatment with serotonin receptor antagonist Cyproheptadine (1 mg/kg, i.p; 47.33 ± 2.25s and 113.50 ± 3.83s (during phase I i.e. 0-5 min) and 26.67 ± 3.83s and 88.17 ± 7.27s (during phase II i.e. 20-30 min) in the AEBM-treated and Cyproheptadine pre-treated AEBM groups, respectively). The % increase in tail flick latency with AEBM was prevented by prior treatment with the non-selective opioid receptor antagonist naloxone (2mg/kg, i.p; 282.35 and 107.35 in the AEBM-treated and naloxone-treated groups, respectively). Our results indicate, that the endogenous adrenergic, serotonergic and opioidergic systems are involved in the analgesic mechanism of action of the aqueous extract of Bacopa monniera.
    No preview · Article · Mar 2011 · International journal of Ayurveda research
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