Behavioral and neuroanatomical assessment of amitriptyline in the treatment of chronic pain following peripheral nerve injury in the rat.
Date
1999
Authors
Esser, Michael J.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
The present study was designed to determine whether amitriptyline, a prototypical tricyclic antidepressant, could produce pain-alleviating effects in a rat model of neuropathic pain. Nerve injury was produced by unilateral spinal nerve ligation and this resulted in persistent stimulus-evoked neuropathic pain symptoms (tactile allodynia and thermal hyperalgesia). Following acute systemic administration, amitriptyline and to a lesser extent desipramine, reversed thermal hyperalgesia in the injured paw. The anti-hyperalgesic effect of systemic amitriptyline, but not desipramine, was blocked by acute caffeine. Spinal administration of amitriptyline produced an anti-hyperalgesic effect that was not blocked by caffeine. An immediate anti-hyperalgesic effect was observed following local peripheral administration of both amitriptyline and desipramine. The local administration of caffeine blocked the actions of amitriptyline but not desipramine. Neither amitriptyline nor desipramine exerted any anti-allodynic effect, but amitriptyline produced hyperaesthesia in the contralateral paw. A time course analysis was made of the immunoreactive expression of the 27 kDa heat shock protein (Hsp27-IR), neuropeptide Y (NPY-IR), and substance P (SP-IR) following nerve injury. Changes in Hsp27-IR were first apparent at 4 days in laminae I through III in the L5 to S2 segmental region of the ipsilateral dorsal horn, were most intense by 12 days, and declined by 180 days. An increase in NPY-IR in the same regions paralleled that of Hsp27-IR, but was offset by a 2--3 day delay. Decreased SP-IR was observed in the superficial laminae of the ipsilateral spinal dorsal horn by 7 days, was greatest after 12 days, and was still evident after 180 days. Both Hsp27-IR and NPY-IR were increased in the dorsal columns and the gracile nucleus by 17 days and persisted to 180 days, but no changes were observed in SP-IR in these regions. A non-invasive chronic drug paradigm (in drinking water) was used to study the behavioral and immunohistochemical effects of chronic amitriptyline alone, and in combination with chronic caffeine. Chronic amitriptyline decreased the expression of thermal hyperalgesia, an effect that was blocked by the concomitant consumption of chronic caffeine. While having no effect on static tactile allodynia of the ipsilateral paw, chronic amitriptyline caused tactile hyperaesthesia in the contralateral paw, an effect that was exacerbated by concomitant chronic caffeine. These behavioral effects were reflected in decreases in Hsp27-IR and NPY-IR in the deeper laminae of ipsilateral spinal dorsal horn.
The results of this thesis suggest that acute and chronic amitriptyline are effective against stimulus-evoked thermal hyperalgesia, and this effect is partially achieved through manipulation of endogenous adenosine levels. The symptom-specific action, and adenosine link in the effect of amitriptyline may be important clinical considerations governing its use in neuropathic pain. Also, the mirrored effects on Hsp27-IR and NPY-IR in the spinal dorsal horn suggest that these two markers may be sensitive indicators of chronic drug manipulation of the mechanisms underlying the development and maintenance of neuropathic pain.
Thesis (Ph.D.)--Dalhousie University (Canada), 1999.
The results of this thesis suggest that acute and chronic amitriptyline are effective against stimulus-evoked thermal hyperalgesia, and this effect is partially achieved through manipulation of endogenous adenosine levels. The symptom-specific action, and adenosine link in the effect of amitriptyline may be important clinical considerations governing its use in neuropathic pain. Also, the mirrored effects on Hsp27-IR and NPY-IR in the spinal dorsal horn suggest that these two markers may be sensitive indicators of chronic drug manipulation of the mechanisms underlying the development and maintenance of neuropathic pain.
Thesis (Ph.D.)--Dalhousie University (Canada), 1999.
Keywords
Biology, Neuroscience., Health Sciences, Pharmacology.