Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of
neuropathic pain, such as
tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs,
doxepin and
amitriptyline, in naïve animals and in a model of
neuropathic pain and to determine the role of
cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI),
doxepin and
amitriptyline attenuated the symptoms of
neuropathic pain and diminished the CCI-induced increase in the levels of spinal
interleukin (IL)-6 and -1β
mRNA, but not the
protein levels of these
cytokines, measured on day 12. Unexpectedly, chronic administration of
doxepin or
amitriptyline for 12 days produced
allodynia and
hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and
IL-6 mRNA, however, the
protein levels of these pronociceptive factors were increased. The administration of
ondansetron (
5-HT3 receptor antagonist) significantly weakened the
allodynia and
hyperalgesia induced by both
antidepressants in naïve mice; in contrast,
yohimbine (α2-
adrenergic receptors antagonist) did not influence these effects.
Allodynia and
hyperalgesia induced in naïve animals by
amitriptyline and
doxepin may be associated with an increase in the levels of pronociceptive
cytokines resulting from 5-HT3-induced
hypersensitivity. Our results provide new and important information about the possible side effects of
antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for
therapy.