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

Annals of Neurology (Impact Factor: 11.91). 02/1983; 13(2):160-4. DOI: 10.1002/ana.410130209
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ABSTRACT 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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    • "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.
    Pain 07/2012; 153(9):1871-82. DOI:10.1016/j.pain.2012.05.028 · 5.84 Impact Factor
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    • "Several TCA compounds (Rigal et al. 1983; Taiwo et al. 1985; Max et al. 1987; Sacerdote et al. 1987; Ventafridda et al. 1990; Sawynok and Reid 1992; Gatch et al. 1998), including amitriptyline (Malseed and Goldstein 1979; Liu and Wang 1981; Botney and Fields 1983; Taiwo et al. 1985; Sacerdote et al. 1987; Ventafridda et al. 1990; Eisenach and Gebhart 1995; Galeotti et al. 1996; Luccarini et al. 2004), enhance morphine-induced analgesia in animal models. This is consistent with clinical data, which has demonstrated that several TCAs potentiate morphine-induced analgesia in humans (Levine et al. 1986; Gordon et al. 1993). "
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    ABSTRACT: 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.
    Neuroscience 02/2011; 175:315-27. DOI:10.1016/j.neuroscience.2010.11.057 · 3.33 Impact Factor
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    • "Korzeniewska - Rybicka and Plaznik , 1998 ) , as well as activation of the opioid system ( Biegon and Samuel , 1980 ; Botney and Fields , 1983 ; Sacerdote et al . , 1987 ) have been suggested as possible mechanisms . "
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    ABSTRACT: Neuropathic pain, a chronic disabling pain arising from nerve injury, develops a central component. In brain neurons, tumor necrosis factor-alpha (TNF) levels intensify and TNF-inhibition of norepinephrine (NE) release, dependent upon alpha(2)-adrenergic activation, amplifies during neuropathic pain onset. TNF-inhibition of NE release transforms to facilitation in the hippocampus of rats administered antidepressants (treat neuropathic pain), contemporaneous with decreased neuron TNF. Therefore, adrenergic drugs inhibit increased pain sensitivity (hyperalgesia) by decreasing TNF production, thereby inducing increased NE release. This study examined TNF- and alpha(2)-adrenergic-regulated NE release from hippocampal slices during both the onset and dissipation of hyperalgesia during sciatic nerve chronic constriction injury (CCI). The enhanced inhibition of NE release by TNF at peak hyperalgesia (day-8) transformed to facilitation of NE release at days 12, 14, 16, and 21 post-CCI, corresponding to dissipation of hyperalgesia. Chronic antidepressant drug administration alone to rats results in similar findings. Rats administered the antidepressant amitriptyline (10 mg/kg, i.p., 60 min) at day-8 post-CCI, no longer exhibited hyperalgesia. Interestingly, the presynaptic response to TNF transformed to facilitation of NE release. While TNF directs the development of hyperalgesia, it is also involved in the resolution of pain, a possible mechanism for management of chronic pain.
    Neuropharmacology 04/2005; 48(3):448-60. DOI:10.1016/j.neuropharm.2004.11.001 · 4.82 Impact Factor
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