rotonin receptor inhibitor—cypotolamine on endogenous opiate peptide concentration in spinal cord. Cypotolamine injection denotes the beginning of cypotolamine administration. Cypotolamine 100 ng group (○, n = 8): the animal was given 100 ng cypotolamine into the spinal cord; Cypotolamine 50 ng group (×, n = 8): the animal was given 50 ng cypotolamine into the spinal cord; Control group (▲, n = 8): the animal was not given cypotolamine into the spinal cord. The data are expressed as mean ± standard error mean (SEM). *P < 0.05, **P < 0.01 and ***P < 0.001 are used for the comparison of the change of L-enkephaline, β-endorphin or dynorphin A1-13 concentration from cypotolamine 100 ng group or cypotolamine 50 ng group and control group.

in 5 min (P < 0.001), 2.9 ± 1.3 pg/mg in 10 min (P < 0.001) and 4.2 ± 1.4 pg/mg in 20 min (P < 0.01); Administration of 50 ng cypotolamine into the spinal cord decreased DynA1-13 concentration in the spinal cord from 6.5 ± 1.8 pg/mg (tissue weight) to 3.1 ± 1.0 pg/mg in 5 min (P < 0.001), 4.8 ± 1.3 pg/mg in 10 min (P < 0.01) and 5.8 ± 1.4 pg/mg in 20 min; In control group, DynA1-13 concentration did not changed (Figure 3(c)).

4. Discussions

Serotonin is an important neurotransmitter to regulate the pain process in the spinal cord through 5-HT receptor. 5-HT1/2A/2C and 5-HT1/2C receptors increases the descending facilitation mechanisms induced by incision in the ipsilateral paw; 5-HT2A/3 receptors contribute to descending pronociceptive pathways conveyed by lamina X spinal neurons [19]. The descending serotonergic pathways and spinal 5-HT7 receptors play a crucial role in the antinociceptive effects [20].

Endogenous opiate peptide system is involved in the serotonin effecting pain modulation. Endogenous opiate peptide may partly act as a necessary mediator for the serotonin-induced suppression on the spinal transmission of nociceptive input [21,22]. Some studies have pointed that endogenous opiate peptide is involved in serotoninproduced antinociception at the spinal level using the tail-flick assay, which effect may be mediated through different types of opiate receptors [14]. Combination of serotonin and δ-selective opiates is more effective in suppressing noxiously evoked activity than combinations with μ-selective opiates [23]. The present study showed that 1) pain stimulation increased not only L-Ek, β-Ep, DynA1-13 concentrations but also serotonin and 5-HIAA concentrations in the spinal cord significantly; 2) serotonin increased L-Ek, β-Ep and DynA1-13 concentrations in the spinal cord in a dose-dependent manner; 3) cypotolamine, a serotonin receptor antagonist decreased L-Ek, β-Ep and DynA1-13 concentrations in the spinal cord. The data suggested that the antinociceptive role of serotonin at spinal level was relating with the endogenous opiate peptide system through serotonin receptors. Our previous study has shown that pain stimulation can influence the endogenous opiate peptide and serotonin system in the nucleus raphe magnus [24].

Chronic nerve injury evoked hypernociception may be contributed by genetic differences of descending serotonergic inhibitory control [25]. Opiates mediates their stimulatory effects on stimulate prolactin release, at least in part, through a serotonergic mechanism in adult rats [26]. Serotonin may influence the gene expression or peptide synthesis process to act the endogenous opiate peptide system in spinal cord. However, it needs to be studied in the near further.

In conclusion, the present study makes it clear that 1) the spinal cord releases endogenous opiate peptides and serotonin during pain process; 2) serotonin enhances, whereas the serotonin receptor antagonist inhibits the spinal cord release of endogenous opiate peptides. The data indicated that the antinociceptive role of serotonin at spinal level was relating with endogenous opiate peptide system via serotonin receptors.

5. Acknowledgements

This work was supported by Xinxiang Medical University, Subei People’s Hospital of Jiangsu Province and grants from National Natural Science Foundation of China (81100956/H0912).

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NOTES

*Corresponding author.

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