J Anesth Perioper Med. 2014;1(2):90-96. https://doi.org/10.24015/ebcmed.japm.2014.0014

Melanocortin 4 Receptor Is Involved in the Development of Morphine Tolerance

Hong-Mei Xu1*, Ze-Jun Niu1*, Hai-Chen Chu1, and Xue-Feng Zhang2

From the 1Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China; 2The Stem cell Center, The Affiliated Hospital of Qingdao University,Qingdao, China.

*Contributed equally to thiswork.

Correspondence to Dr. Hai-Chen Chu at haichen0312@aliyun.com.

EBCMED ID: ebcmed.japm.2014.0014 DOI: 10.24015/ebcmed.japm.2014.0014


Prolonged morphine treatment usually results in the development of analgesic tolerance. Melanocortin 4 receptor (MC4R) is involved in the development of morphine tolerance. The aim of this study was to examine the effects of an MC4R antagonist, HS014, on MC4R-mediated hyperalgesia and on microglia and cytokine expression in the spinal cord of rat during morphine tolerance.

Thirty rats were assigned randomly to the N group, M group, HM group, NM group and HN group (N=6 in each group). Rats received 5-day treatment with saline (N group) or morphine (M group). Rats were given an intrathecal injection (i.t.) of HS014 (HM group) or saline (NM group) at 15 minutes prior to the morphine challenge. In the HN group, rats were injected with HS014 at 15 minutes prior to the saline. To observe the effect of HS014 on the development of morphine tolerance, morphine-tolerant rats were assigned to M1 group, M2 group, M3 group and N group on day 6 (N=6 in each group). The morphine-tolerant rats in M1 group, M2 group and M3 group received morphine (10 mg/kg, i.p.), HS014 (5 μg, i.t.) and HS014 (5 μg, i.t.) followed 15 minutes later by injection of morphine (10 mg/kg, i.p.), respectively. Control rats (N group, N=6) were injected with saline under identical conditions. Hot-plate test and immunochemistry were used to examine the withdrawal latency and inflammatory cytokines.

Morphine treatment (10 mg/kg, i.p. twice daily) over 5 days induced tolerance as reflected by a significant reduction of withdrawal latency from 29.67 ± 1.81 s to 8.67 ± 1.70 seconds in the hot- plate test. Repeated HS014 injection prior to morphine administration inhibited the development of morphine tolerance. Furthermore, a single administration of HS014 restored morphine analgesic potency in morphine-tolerant rats. Immunohistochemical staining showed that the administration of HS014 during the induction of morphine tolerance inhibited the activation of microglia, reduced the expression of proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α, and increased the expression of antiinflammatory cytokines (IL-10) at the L5 lumbar spinal cord.

HS014 attenuates the development of antinociceptive tolerance following chronic administration of morphine by inhibiting microglial activation and reducing the expression of IL-1, IL-6 and TNF-α.

Article Type
Original Article

Declaration of Interests
The authors report no other conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This research was supported by the grant (No. 2013GSF11863) from Development Plan of Science and Technology of Shandong Province.

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