A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects

Abstract

N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.

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“…Different kinds of pain have some characteristics in common, such as positive features (e.g., spontaneous pain, hyperalgesia, and allodynia) and negative features (e.g., weakness, sensory loss, and hypoesthesia) 2 . Although pharmacological control of pain‐related diseases has achieved certain success, the medications’ potential side effects could not be ignored 3 . Therefore, it is highly significant to develop new analgesic strategies to effectively relieve pain with fewer adverse effects.…”

“…2 Although pharmacological control of pain-related diseases has achieved certain success, the medications' potential side effects could not be ignored. 3 Therefore, it…”

Marine natural products

“…A conantokin-T variant, con-T[M8Q] exhibits potent activity in mouse models of morphine-dependence. 667…”

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“…Similarly, Qiang and colleagues studied the α-conotoxin Lv1d, from the same species, observing that it showed analgesic effects in both the murine hotplate test and the formalin test, suggesting it was also effective for inflammatory pain [121,122]. Liu and colleagues communicated that a helical conantokin peptide Con-T[M8Q] (104), purified from the genus Conus, was an antagonist of the GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAR), which showed inhibition of physiological and psychological morphine dependence and attenuated withdrawal symptoms, as examined by naloxone-induced jumping and conditioned place preference tests in a murine model of morphine addiction [123].…”