Neurotropin (NTP)(®), a non-
protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, is used clinically for the treatment of
neuropathic pain. Moreover, NTP may activate the descending
pain inhibitory system. Depression-like behavior is often complicated by
chronic pain. However, little is known about NTP-mediated prevention of
mood disorders in
chronic pain and its molecular mechanisms. We aimed to investigate the effects of NTP on
brain-derived neurotrophic factor (
BDNF)-mediated signaling and gene expression in
chronic pain. In addition, these effects of NTP were compared with
pregabalin which is an
anticonvulsant,
anxiolytic analgesic used to treat
neuropathic pain and
fibromyalgia. A chronic constriction injury model was established in Sprague-Dawley rats. The
pain response was assessed using a paw withdrawal latency (PWL) test and depression was assessed by the immobility time in a forced swim test (FST). NTP was orally administered in two doses of 50 NU (
Neurotropin Unit) and 100 NU/kg for 7 days from day 7 after injury. To measure the
analgesic and anti-depressant effects of NTP, either
K252a (a
tyrosine kinase inhibitor), or 5,7-dihydroxy
tryptamine (5,7-DHT, a selective toxin for 5-HTergic neurons) was administered by intracerebroventricular injection. Changes in pERK1/2 and pCREB (immunohistochemistry),
5-HT, and
BDNF protein level (ELISA) and
BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC) and in the rostral ventromedial medulla (RVM) 14 days after injury. After injury, the rats showed a decrease in PWL associated with the increase in time of immobility in FST. In this injury model, NTP blocked both the decrease in PWL and the increase in the FST, while
pregabalin (10 mg/kg, po.) did not affect the increase in the FST. These effects of NTP were reversed by
K252a, and 5,7-DHT. The
analgesic effects of
pregabalin were not reversed by
K252a. NTP normalized the injury-induced excessive activation of pERK1/2 associated with decreased pCREB and
BDNF mRNA in the ACC and in the RVM, and these changes were reversed by 5,7-DHT. In contrast,
pregabalin did not affect either pCREB or
BDNF levels in the
chronic pain model. NTP ameliorated
chronic pain and
pain-related depression by normalizing the induction of
BDNF associated with the 5-HTergic system.
Pregabalin showed the
analgesic effects but had no effects on either depression or the
BDNF pathway. These results suggest that NTP may represent an additional
drug strategy for
chronic pain associated with depression.