| Cancer induced pain which is one kind of common clinical chronic pathological syndrome, has been reported that it significantly decreased the patients’quality of life. Approximately 30-50% of all cancer patients will experience moderate to severe pain, and 75-95% of patients with advanced-stage or metastatic cancer will experience substantial, life-altering cancer induced pain. Hence, how to relieve cancer pain now has become one of clinical subjects to improve the patients’quality of life.As one of the representative opioid analgesics,morphine has a very good effect on acute and chronic pain. The medical experts suggest that morphine should be used early and enough to treat patients with cancer pain, and they also emphasis that the doses of morphine should not be restricted. The world health organization (WHO) puts a country’s morphine consumption as a measure of pain control level. Therefore, morphine is still the gold standard treatment of pain. Morphine expresses a powerful analgesic effect to relieve cancer pain in patients through its action on the central opioid receptors. However, some evidences suggest that long-term morphine treatment may lead to cellular and molecular adaptations, which results in pharmacological tolerance. Indeed, morphine tolerance restricts its use in chronic pain. It can decrease the analgesic and lead to hyperalgesia when morphine used in an unreasonable way. Thus, morphine tolerance has become a severe clinical issue.Previous studies for’morphine tolerance were almost based on animal models either in absence of painful tissue injury, or in neuropathic pain. However, there are few reports about morphine tolerance in cancer pain. To investigate whether morphine tolerance happens in rats with bone cancer pain is one of the present subjects.There are many similarities between morphine tolerance and pathological pain. First, they both perform hyperalgesia and allodynia. The former means that the sensitivity of noxious stimuli is obviously enhanced and the latter stands for that gentle stimulus also causes pain in physiological conditions. Second, there are neural plasticity changes in the spinal cord. It has reported that glia is activated in the animal models of morphine tolerance. Moreover, morphine tolerance can be delayed when glia activation is inhibited. All of these research indicate that glia activation in CNS may be one of the mechanism of morphine tolerance. At the same time, previous studies have proved that glia activation plays an important role in the initiation and maintainance of pathologic pain. Glia is related with glutamic acid which is a major nociceptive transmission material in CNS including its metabolism, absorbability, synthesis and removel. Inflammatory factors such as Interleukin lbeta (IL-10), Interleukin 6 (Interleukin 6, IL-6), Tumor Necrosis Factor (TNF-α) which are released by glial, can lead to the sensitization of nociceptive transmission neurons and promote the formation of central sensitization. Thus, the mechanism of morphine tolerance in rats with bone cancer pain is another problem we focus on in this article.Minocycline is a half synthetic second generation tetracycline derivatives. It can pass through the blood brain barrier to the central nervous system and play a role in neural protection. As one of the microglia selective inhibitors, minocycline can inhibit microglia activation and reduce the expression of inflammatory factors which lead to decrease hyperalgesia and allodynia. Then, we investigate whether systematic administrated minocycline can decrease hyperalgesia in bone cancer pain and whether the mechanism of its action is associated with the reduced inflammatory factors in the spinal cord.In summary, we first established the rat model with bone cancer pain by unilateral inoculation of Walker256 mammary gland carcinoma. Second, chronic morphine were administrated (10mg/kg, twice daily, s. c.) to rats for five days to elicit morphine tolerance. Third, we chose minocycline to be co-administrated with morphine to investigate its effect on morphine tolerance in rats with bone cancer pain.Results:(I) Chronic morphine successfully elicited pharmacological tolerance in rats with bone cancer pain during the early (day 5-9) and late period (day 14-18). The MPE% in Tail-Flick Test and mechanical response threshold to von Frey hair in rats with bone cancer pain significantly reduced after repeated morphine treatment, which indicated that the analgesic effect of morphine decreased. Multi-morphine treatment group exhibited decreased MPE% in Tail-Flick Test and reduced central time (s) in Open-Field Test than single-morphine treatment group. All of the evidences clarify that repeated morphine produced tolerance in rats with bone cancer pain.(Ⅱ) During the early (day 5-9) period of bone cancer pain, compared to morphine(10mg/kg, s. c.) group, the MPE% of morphine (lOmg/kg, s. c.) co-administrated with different doses of minocycline (50mg/kg, 100mg/kg, 200mg/kg, p. o.)has a trend of increase. Moreover, the MPE% of morphine (10mg/kg,s.c.) co-administrated with minocycline (200mg/kg,p.o.) significantly increased than morphine (10mg/kg, s.c.) on day 5 and 7, (P<0.05). Thus, minocycline could enhance the analgesic action of morphine and delay the morphine tolerance process.(III) Real Time-PCR results showed that there was a increased trend of IL-1β、IL-6 mRNA in the spinal cord in morphine(10mg/kg, s. c.) group compared to NS (same volume with morphine, s. c.) group, which indicated that IL-1β and IL-6 may play an important role in morphine tolerance in rats with bone cancer pain. Compared to morphine(10mg/kg, s.c.) group, IL-1β, IL-6 and TNF-α mRNA of morphine(10mg/kg, s. c.)co-administrated with minocycline (200mg/kg, p. o.)group significantly reduced in the spinal cord, which suggested minocycline delayed morphine tolerance in rats with bone cancer pain through down-regulation of inflammatory factors such as IL-1β, IL-6 and TNF-α.Conclusion:In this study, chronic morphine successfully elicited pharmacological tolerance in the model of bone cancer pain during the early(day 5-9)and late period (day 14-18). Inflammatory factors including IL-1β and IL-6 may be one of important factors contributed to the mechanism of morphine tolerance. Systematic minocycline co-administrated with morphine enhanced the analgesic effect and delayed the process of morphine tolerance in rats with bone cancer pain. It suggested that this effect might be associated with microglia and inflammatory factors such as IL-1β, IL-6 and TNF-α. |
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