Although clinically well controlled at the metabolic level, type I diabetes resulting from an insufficient insulin secretion remains the cause of severe complications. In particular, diabetes can be associated with
neuropathic pain which fails to be treated by classical
analgesics. In this study, we investigated the efficacy of a novel
non opioid analgesic,
cizolirtine, to reduce
mechanical hyperalgesia associated with
streptozotocin (STZ)-induced diabetes, in the rat.
Cizolirtine was compared to
paroxetine, an
antidepressant drug with proven efficacy to relieve
painful diabetic neuropathy. Under acute conditions,
cizolirtine (30 and 80 mg/kgi.p.) significantly increased paw withdrawal and vocalization thresholds in the paw pressure test in diabetic rats displaying
mechanical hyperalgesia. The antihyperalgesic effects of
cizolirtine persisted under chronic treatment conditions, since pre-diabetes thresholds were recovered after a two week-treatment with the
drug (3 mg/kg/day, s.c.). In this respect,
cizolirtine was as efficient as
paroxetine (5 mg/kg per day, s.c.) which, however, was inactive under acute treatment conditions. Measurements of the spinal release of
calcitonin gene-related peptide (CGRP) through intrathecal perfusion under
halothane-
anesthesia showed that acute administration of
cizolirtine (80 mg/kg, i.p.) significantly diminished (-36%) the
peptide outflow in diabetic rats suffering from
neuropathic pain. This effect as well as the antihyperalgesic effect of
cizolirtine were prevented by the alpha(2)-adrenoreceptor antagonist
idazoxan (2 mg/kg, i.p.). These data suggest that the antihyperalgesic effect of
cizolirtine in diabetic rats suffering from
neuropathic pain implies an alpha(2)-adrenoceptor-dependent presynaptic inhibition of CGRP-containing primary afferent fibers.