Effects Of Caffeine On Neuropathic Pain And Gabapentin In Rats And Its Related Mechanism

ObjectiveCaffeine can significantly increase the analgesic’s effect on acute pain. However, whether caffeine enhances the analgesicon chronic pain is still not clear. Research shows that low doses of caffeine inhibit antinociception of several drugs on neuropathic pain. It may owe to the non-selective adenosine receptor (AR) of caffeine. Nowadays, gabapentin and its derivatives are widely used in relieving neuropathic pain. Our research is aiming to investigate the potential analgesic effect of caffeine or gabapentin alone and the combination both of them by monitoring the behavior of chronic constriction injury of the sciatic nerve (CC1) in rats. Meanwhile, we explore the expression ofadenosine A2A receptor and PKA in spinal dorsal horn.Methods60male SD rats were randomly divided into ten groups (n=6):no treatment group (Naive), sham operation group (Sham), chronic constriction injury of the sciatic nerve injury group (CCI). There were8subgroups in CCI group:normal saline treated group (NS), gabapentin100mg/kg group (GBP), caffeine10,30,100mg/kg groups (CAF10,30,100), combination of gabapentin100mg/kg and caffeine10,30,100mg/kg groups (GBP+CAF10,30,100), n=6. The mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) were monitored to assess pain behavior before surgery and on days post operative3,7and14days. All drugs were injected intraperitoneally once a day on7consecutive days from the seventh day after surgery. All rats were sacrificed on thepostoperative14-day and L4-L6spinal cord dorsal horn were kept for molecular biology experiment. To investigate adenosine A2A receptor and the gene of adenosine A2A receptor and PKA in spinal cord dorsal horn through Western Blotting and Real-time PCR.ResultsLow and moderate doses of caffeine (10,30mg/kg) have no obvious therapeutic effect on neuropathic pain.High doses of caffeine (100mg/kg) have analgesic effect on neuropathic pain and it has statistical significance (P<0.05). In molecular level, Real-time PCR reveals that in spinal dorsal horn the gene expression of adenosine A2A (Adora2a) and PKA (Prkaca) are increased. Western Blot suggests that in spinal dorsal horn low dose of caffeine (10mg/kg) increases the expression of adenosine A2A receptor. Otherwise, high dose of caffeine (100mg/kg) decreases the expression of adenosine A2A receptor. In the combination of gabapentin and caffeine, outcomes show that low and moderate doses of caffeine (10,30mg/kg) attenuate the analgesic effect of gabapentin. However, high dose of caffeine (100mg/kg) does not affect the analgesic effect of gabapentin on neuropathic pain. In molecular level, Real-time PCR reveals that in spinal dorsal horn the gene expression of adenosine A2A (Adora2a) and PKA (Prkaca) have no differences. Western Blot suggests that in spinal dorsal horn the expression of adenosine A2A receptor are decreased in the combination of two drugs, but none of them has statistical significance (P>0.05).ConclusionsIn the treatment of neuropathic pain, high dose of caffeine has analgesic effect.The molecular mechanism of analgesia is that high doses of caffeine inhibit adenosine A2A receptor, it decreases the activation of cAMP-dependent pathway.Gabapentin can effectively alleviate neuropathic pain, but low dose of caffeine will attenuate the analgesic efficacy. The mechanism may be not involving the cAMP-dependent pathway. As a conclusion, coffee or drinks containing caffeine should be avoided while using gabapentin on neuropathic pain.