Study On Gabapentin And Morphine Tolerance:Can Gabapentin Antagonize The Tolerance To Morphine Analgesia

Morphine is a highly potent opiate analgesic drug and it is clinically used in the treatment of moderate to severe pain. However, long-term administration of opioids produces negative health consequences such as abuse and addiction. Prolonged administration of opioids is also associated with the development of antinociceptive tolerance; its analgesic potency fades rapidly upon frequent administration so that larger dose of morphine is required to maintain the same effect. For reducing the amount of morphine, combination therapy is well suited for pain management, and has been recommended by clinical. The previous studies have demonstrated that gabapentin (GBP) can antagonize morphine tolerance in naive or acute pain animals. Actually, the clinical morphine antinociceptive tolerance occurs only in patients with chronic pain. We, therefore, investigated whether GBP prevents morphine tolerance in a tetanic sciatic stimulation (TSS)-induced neuropathic pain model in rats. The main findings were as followed:1、Prolonged administration of gabapentin failed against morphine tolerance in neuropathic painConsistent with our previous reports, tetanic sciatic stimulation induced allodynia and thermal hyperalgesia. Consecutive 9 days administration of morphine (sc 10mg/kg twice daily) produces significant analgesic tolerance. The test doses of morphine (i.p. 5mg/kg) lack of analgesic effect in 7-9 days. Surprisingly, the combination of gabapentin (GBP,50mg/kg, i.p. twice daily for 9 consecutive days) and morphine, in addition to the first application to generate a stronger analgesic effect, GBP failed to prevent or delay the morphine tolerance; moreover, the cumulative inhibitory effect of gabapentin on neuropathic pain are completely lost after combination of administration gabapentin and morphine.2、Blocking cholecystokinin receptor CCK-2 against morphine tolerance and save the analgesic effect of gabapentinCholecystokinin receptor (CCK) is an endogenous anti-opioid substance, the increased levels of CCK-8 in vivo are considered to be one of the reasons morphine tolerances. In morphine tolerance animals, we continuously give the 9th day of morphine, a single intrathecal administration of CCK-8 receptor CCK-2R antagonist LY225910 (25 ng) can significantly save the analgesic effect of morphine and morphine combine with GBP; prolonged administration of morphine and GBP, at the same time, intrathecal osmotic pump continued to give LY225910 (9-10 days) can slow the occurrence of analgesic tolerance in the rat model of neuropathic pain.3、the interaction between CCK-2R and calcium channel α2δ-1 subunit may be involved in the inhibition of morphine tolerance to the analgesia effect of gabapentin.As we known, the target of GBP is α2δ-1 subunit of voltage-dependent calcium channels. Immunohistochemistry show subunits α2δ-1 and CCK-2R are co-expressed in DRG neurons and the dorsal horn of the spinal cord; Co-immunoprecipitation results show that α2δ-1 subunit and CCK-2R have direct interaction in the spinal cord and DRG tissue. Further, we examine the expression level of CCK-2R and α2δ-1 subunit in the spinal cord under the neuropathic pain model and morphine analgesic tolerance conditions. Western blot analysis showed that the TSS can increase CCK-2R level in the spinal cord and DRG, repeatedly injected with morphine can further increase the level of CCK-2R, α2δ-subunit expression in the spinal cord can be suppressed by GBP, but in morphine tolerance, GBP is not able to reduce spinal cord α2δ-1 subunit expression levels. Finally, we found that direct intrathecal injection of CCK-8 (300ng/15ul) can produce neuropathic pain-like behavior in normal rats, GBP not inhibition of the hyperalgesic behavior.In summary, the study has shown that in tetanic sciatic stimulation induced neuropathic pain model, single time of gabapentin (GBP) can enhance morphine analgesic effect, but after chronic exposure of morphine, GBP have no impact on morphine tolerance. However, f GBP alone provides stable analgesic effect in neuropathic pain, even after a prolonged administration. Multi-injection of morphine could counteract with the analgesic effect of GBP, CCK-8 and its receptor CCK-2R may be involved in this process.