Depression is a well-recognised effect of long-term treatment with
interferon-alpha (IFN-α), a widely used treatment for chronic viral
hepatitis and
malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as
headache and
joint pain have also been reported following IFN-α treatment. The
endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system. The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the
endocannabinoid system. Furthermore, the effects of modulating peripheral
endocannabinoid tone on inflammatory
pain-related behaviour in the IFN-α model was examined. Repeated IFN-α administration (8000 IU/g/day) to male C57/Bl6 mice increased immobility in the forced swim test and reduced
sucrose preference, without altering
body weight gain or locomotor activity, confirming development of the depressive-like phenotype. There was no effect of repeated IFN-α administration on latency to respond in the hot plate test on day 4 or 7 of treatment, however,
formalin-evoked nociceptive behaviour was significantly increased in IFN-α treated mice following 8 days of IFN-α administration. 2-Arachidonoyl
glycerol (2-AG) levels in the periaqueductal grey (PAG) and rostroventromedial medulla (RVM), and
anandamide (AEA) levels in the RVM, were significantly increased in IFN-α-, but not saline-, treated mice following
formalin administration. There was no change in
endocannabinoid levels in the prefrontal cortex, spinal cord or paw tissue between saline- or IFNα-treated mice in the presence or absence of
formalin. Furthermore, repeated IFN-α and/or
formalin administration did not alter
mRNA expression of genes encoding the
endocannabinoid catabolic
enzymes (
fatty acid amide hydrolase or
monoacylglycerol lipase) or
endocannabinoid receptor targets (CB1, CB2 or PPARs) in the brain, spinal cord or paw tissue. Intra plantar administration of
PF3845 (1 μg/10 μl) or
MJN110 (1 μg/10 μl), inhibitors of AEA and 2-AG catabolism respectively, attenuated
formalin-evoked
hyperalgesia in IFN-α, but not saline-, treated mice. In summary, increasing peripheral
endocannabinoid tone attenuates inflammatory
hyperalgesia induced following repeated IFN-α administration. These data provide support for the
endocannabinoid system in mediating and modulating heightened
pain responding associated with IFNα-induced depression.