Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition

Yong-Xiang Wang, Xiao-Fang Mao, Teng-Fei Li, Nian Gong, Ma-Zhong Zhang, Yong-Xiang Wang, Xiao-Fang Mao, Teng-Fei Li, Nian Gong, Ma-Zhong Zhang

Abstract

Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation's opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine. Its mechanical antiallodynia was partially (40% or 60%) and completely (100%) attenuated by spinal μ-opioid receptor (MOR) antagonism or norepinephrine depletion/α2-adrenoceptor antagonism and combined antagonism of MORs and α2-adenoceptors, respectively. In contrast, antagonism of spinal κ-opioid receptors (KORs) and δ-opioid receptors (DORs) or depletion of spinal serotonin did not significantly alter dezocine antiallodynia. In addition, dezocine-delayed antiallodynic tolerance was accelerated by spinal norepinephrine depletion/α2-adenoceptor antagonism. Thus dezocine produces antihypersensitivity activity through spinal MOR activation and norepinephrine reuptake inhibition (NRI), but apparently not through spinal KOR and DOR activation, serotonin reuptake inhibition or other mechanisms. Our findings reclassify dezocine as the first analgesic of the recently proposed MOR-NRI, and reveal its potential as an alternative to as well as concurrent use with morphine in treating pain.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. The chemical structures of pentazocine…
Figure 1. The chemical structures of pentazocine and dezocine.
Figure 2
Figure 2
Time-course (A,B) and cumulative dose-response curves (C–F) of subcutaneous injection of dezocine and morphine antihypersensitivity activity in neuropathy. Neuropathic rats, induced by tight ligation of L5/L6 spinal nerves, received subcutaneous injection of dezocine or morphine. Data are summarized as means ± SEM (n = 6 and 10 in each group in the time-course and dose-response study, respectively). *P < 0.05 vs. the normal saline control, by repeats-measured two-way ANOVA followed by post-hoc student-Newman-Keuls tests.
Figure 3
Figure 3
Effects of the specific opioid receptor subtype antagonists, given intrathecally, on dezocine (A–C) and morphine antinociception (D–F) in neuropathic rats, induced by tight ligation of L5/L6 spinal nerves. Data are presented as means ± SEM (n = 6–8 in each group). *P < 0.05 vs. the respective normal saline + dezocine and normal saline + morphine group, by repeats-measured two-way ANOVA followed by post-hoc student-Newman-Keuls tests.
Figure 4
Figure 4
Effects of dezocine and morphine, given subcutaneously, on spinal levels of norepinephrine (A), serotonin (B) and dopamine (C) in neuropathic rats, induced by tight ligation of L5/L6 spinal nerves. Effects of the specific norepinephrine depletor 6-hydroxydopamine (6-OHDA), serotonin depletor p-cholrophenylalanine (PCPA) (D, E) and 5-hydroxytryptamine (5-HT) receptor antagonist metergoline (F,G), given intrathecally, on dezocine and morphine mechanical antiallodynia in neuropathy. Data are presented as means ± SEM (n = 6 in each group). *P < 0.05 vs. the normal saline control or respective normal saline + dezocine and normal saline + morphine group, by one-way or repeats-measured two-way ANOVA followed by post-hoc student-Newman-Keuls tests.
Figure 5
Figure 5
Effects of the selective noradrenergic α-adrenoceptor antagonist phentolamine (A,B), β-adrenoceptor antagonist propranolol (C,D), α1-adrenoceptor antagonist prazosin, α2-adrenoceptor receptor antagonist yohimbe, and the mixture of the μ-opioid receptor antagonist CTAP and yohimbe (E), given intrathecally, on dezocine and morphine antinociception in neuropathic rats, induced by tight ligation of L5/L6 spinal nerves. Data are presented as means ± SEM (n = 6 in each group). *P < 0.05 vs. the normal saline control or respective normal saline + dezocine and normal saline + morphine group, by repeats-measured two-way ANOVA followed by post-hoc student-Newman-Keuls tests.
Figure 6
Figure 6
Mechanical antiallodynic tolerance development of dezocine, morphine and their combination, given subcutaneously, in neuropathic rats, induced by tight ligation of L5/L6 spinal nerves (A). Effects of the specific norepinephrine depletor 6-hydroxydopamine (6-OHDA), serotonin depletor p-cholrophenylalanine (PCPA) (B,C), and the selective noradrenergic α1-adrenoceptor antagonist prazosin and α2-adrenoceptor receptor antagonist yohimbe (D), given intrathecally, on dezocine and morphine antinociceptive tolerance in neuropathy. Data are presented as means ± SEM (n = 6 in each group). *P < 0.05 vs. the normal saline control or respective normal saline + 6-OHDA and normal saline + PCPA group, by repeats-measured two-way ANOVA followed by post-hoc student-Newman-Keuls tests.

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