Acute amitriptyline in a rat model of neuropathic pain: differential symptom and route effects
ABSTRACT The present study was designed to determine whether amitriptyline, a prototypical tricyclic antidepressant, could produce pain relieving properties in a rat model of neuropathic pain. Nerve injury was produced by tight ligation of the lumbar 5th and 6th dorsal roots and this resulted in persistent stimulus evoked neuropathic pain symptoms (tactile allodynia and thermal hyperalgesia). Thermal hyperalgesia was measured using a focused light beam directed at the ventral surface of the paw while tactile allodynia was determined using Semmes-Weinstein monofilaments applied to the ventral surface of the paw. Amitriptyline was administered systemically (intraperitoneal), spinally (intrathecal cannula), and locally (subcutaneously) via direct injection into the dorsal surface of the paw. Following systemic administration, amitriptyline completely reversed thermal hyperalgesia (10 mg/kg) in the injured paw. Spinal administration of amitriptyline (60 microg) also produced an antihyperalgesic effect. Interestingly, local administration of amitriptyline (100 nmol) had an immediate antihyperalgesic effect that persisted for 120 min following administration. Amitriptyline had no alleviating effect against mechanical allodynia regardless of the route of administration, but curiously, produced hyperaesthesia in the contralateral paw. These results indicate that in the rat model of spinal nerve ligation, amitriptyline is effective in alleviating thermal hyperalgesia (systemically, spinally and locally) but is ineffective against mechanical allodynia. The peripheral efficacy of amitriptyline suggests the possibility of the development of cream formulations that may be able to increase the local concentration of amitriptyline without increasing the systemic dose and the subsequent occurrence of side effects.
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ABSTRACT: The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies.Pharmacological reports: PR 06/2014; 66(3):459-465. DOI:10.1016/j.pharep.2013.11.004 · 2.17 Impact Factor
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ABSTRACT: Amitriptyline is a tricyclic antidepressant that is also widely used to treat neuropathic pain in humans, but the mechanism of this anti-hyperalgesic effect is unknown. Microglia in the mouse spinal cord become activated in neuropathic pain, and expression of P2X4 receptors by these microglia is increased. Antisense RNA targeting P2X4 receptors suppresses the development of tactile allodynia in rats. This suggests that blockade of P2X4 receptors might be the mechanism by which amitriptyline relieves neuropathic pain. We expressed human, rat and mouse P2X receptors (P2X2, P2X4, P2X7) in human embryonic kidney cells and evoked inward currents by applying ATP. We compared the action of ATP on control cells and cells treated with amitriptyline. Amitriptyline (10 microM), either applied acutely or by pre-incubation for 2-6 h, had no effect on inward currents evoked by ATP (0.3-100 microM) at human P2X4 receptors. At rat and mouse receptors, amitriptyline (10 microM) caused a modest reduction in the maximum responses to ATP, without changes in EC(50) values, but it had no effect at 1 microM. Amitriptyline also had no effects on currents evoked by ATP at rat P2X2 receptors, or at rat or human P2X7 receptors. The results do not support the view that amitriptyline owes its pain-relieving actions in man to the direct blockade of P2X4 receptors.British Journal of Pharmacology 03/2010; 160(1):88-92. DOI:10.1111/j.1476-5381.2010.00683.x · 4.99 Impact Factor
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ABSTRACT: Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity.Chemistry & biology 07/2009; 16(6):644-56. DOI:10.1016/j.chembiol.2009.05.010 · 6.59 Impact Factor