Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides
Highlights
► The concentrations of oxytocin (OXT), leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek) and β-endorphin (β-Ep), not dynorphin A1–13 (DynA1–13) in the PAG perfusion liquid were increased after the pain stimulation. ► The concentrations of L-Ek, M-Ek and β-Ep, not DynA1–13 in the PAG perfusion liquid were decreased by the OXT receptor antagonist. ► The increased pain threshold induced by the OXT was attenuated by naloxone. ► The concentrations of L-Ek, M-Ek and β-Ep, not DynA1–13 in the PAG perfusion liquid were increased by exogenous OXT administration. ► OXT in the PAG participate in pain modulation by influencing the L-Ek, M-Ek and β-Ep rather than DynA1–13.
Introduction
Periaqueductal gray (PAG) is the gray matter located around the cerebral aqueduct within the tegmentum of the midbrain. It plays a role in the descending modulation of pain. The ascending pain fibers of the spinothalamic tract also send information to the PAG via the spinomesencephalic tract [11], [26]. PAG, which is relating with the endogenous opiate system, is a very important neural structure regulating pain process [7], [22], [24], [36].
Oxytocin (OXT), a nonapeptide posterior hormone, is mainly synthesized and secreted in the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN). This hormone, combined with an apparent carrier protein (neurophysin), is transported along the hypothalamo-hypophyseal pathway to the neurohypophysis, where it is stored for subsequent release [14]. The remarkable functions of OXT include uterine contraction during parturition, milk-ejection reflex during lactation, cardiovascular regulation, sex activity, learning and memory [14]. Recently, it has been demonstrated that OXT is relating with the pain modulation. Intraventricular injection (icv) of OXT increases the pain threshold, whereas administration of anti-OXT serum (icv) decreases the pain threshold [31], [32]. Pain stimulation changes OXT concentration in many brain nuclei such as the hypothalamic suprachiasmatic nucleus (SGN), hypothalamic ventromedial nucleus (HVN), thalamic reticular nucleus (TRN), locus coeruleus (LC), raphes magnus nucleus (RMN) and caudate nucleus (CdN) [25], [29], [31], [32].
Our previous study has proven that pain stimulation decreases the OXT concentration in the PAG tissue [31]. Acupuncture not only induces analgesia, but also influences the OXT concentration in the PAG [32]. Our unpublished materials also have demonstrated that (1) intra-PAG injection of 10 ng OXT/1 μl ACSF increased the pain threshold from 5.0 ± 0.4 mA to 9.8 ± 1.3 mA at 10 min (P < 0.001), 8.2 ± 1.1 mA at 20 min (P < 0.001) and 7.1 ± 0.9 mA at 30 min (P < 0.05); and intra-PAG injection of 5 ng OXT/1 μl ACSF increased the pain threshold from 5.2 ± 0.5 mA to 7.6 ± 1.0 mA at 10 min (P < 0.01) and 6.7 ± 0.7 mA at 20 min (P < 0.05); but intra-PAG injection of 1 μl ACSF alone (Control group) did not change the pain threshold; (2) intra-PAG injection of 1 μg OXT receptor antagonist (desGly-NH2, d(CH2)5[d-Tyr2, Thr-sup-4]OVT)/1 μl ACSF decreased the pain threshold from 5.1 ± 0.5 mA to 3.3 ± 0.6 mA at 10 min (P < 0.01) and 3.9 ± 0.5 mA at 20 min (P < 0.05); and intra-PAG injection of 0.5 μg OXT receptor antagonist/1 μl ACSF decreased the pain threshold from 5.2 ± 0.5 mA to 4.3 ± 0.3 mA at 10 min (P < 0.05) and 4.7 ± 0.5 mA at 20 min; but intra-PAG injection of 1 μl ACSF alone (Control group) did not change the pain threshold; and (3) giving the animal 1 min pain stimulation increased OXT concentration in the PAG perfusion liquid to 189.3 ± 22.1% at 10 min (P < 0.001), 86.5 ± 17.5% at 20 min (P < 0.01) and 35.7 ± 14.6% at 30 min, but in the control group OXT concentration in PAG perfusion liquid did not change. OXT in the PAG is involved in the antinociceptive process.
OXT is very similar to arginine vasopressin (AVP) in the structure, synthesis, source and distribution [14]. Intra-PAG microinjection of AVP increases the pain threshold, and local administration of vasopressin receptor antagonist decreases the pain threshold [28]. The antinociceptive role of AVP in the PAG is through endogenous opiate peptides [34], [35]. Histological studies have discovered that there are many OXT-containing fibers and OXT receptors in the PAG [3], [4], [21]. Some experiments have reported that μ- and κ-opiate receptor antagonists can block the antinociceptive effect of intra-PAG injection of OXT [5]. However, it is still not clear that OXT, which is relating with pain process, influences the endogenous opiate peptides in the PAG or not. The present study was tried to investigate the effect of OXT on endogenous opiate peptides in the PAG including leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek), β-endorphin (β-Ep) and dynorphin A1–13 (DynA1–13), so as to understand the mechanism of OXT regulating pain process.
Section snippets
Animals
Adult male Sprague–Dawley rats weighing 180–220 g, which were obtained from Animal Center of Yangzhou University, Yangzhou, Jiangsu, China, were housed with food and water available ad libitum in a colony room under controlled temperature, humidity and a 12 h light/dark cycle (light at 6:00 AM and dark at 6:00 PM). All the procedures were approved by Animal Care Committee of Yangzhou University and conducted according to the guidelines of the International Association for the Study of Pain [37].
Materials
The concentrations of OXT, L-Ek, M-Ek and β-Ep in the PAG perfusion liquid were increased after the pain stimulation
The basal concentrations of OXT, L-Ek, M-Ek, β-Ep and DynA1–13 in the PAG perfusion liquid were 5.2 ± 1.7 pg/ml, 13.3 ± 2.2 pg/ml, 14.5 ± 2.4 pg/ml, 15.6 ± 2.7 pg/ml and 8.9 ± 1.7 pg/ml, respectively.
Pain stimulation not only increased the OXT concentration, but also increased the L-Ek, M-Ek and β-Ep, not DynA1–13 concentrations in the PAG perfusion liquid.
Giving the rat 1 min pain stimulation, OXT concentration in the PAG perfusion liquid increased to 198.7 ± 35.5% at 10 min (P < 0.001) and 108.7 ± 24.8% at 20 min (P <
Discussion
Since Hughes et al. purified and identified L-Ek and M-Ek in 1975 [8], the endorphin had been confirmed in 1976 [10] and dynorphin in 1979 [6]. Endogenous opiate peptides include three series – enkephalin, endorphin and dynorphin [19], which have been proven to participate in the pain modulation [2], [7], [22], [24], [36].
OXT is a peptide of nine amino acids (a nonapeptide): its systematic name is cys–tyr–ile–gln–asn–cys–pro–leu–gly-NH2, which structure is very similar to that of AVP
Acknowledgments
This work was supported by Xinxiang Medical University, Kamp Institute for Medical Research, Jiangsu Su Bei People's Hospital and grants from National Basic Research Program of China (2007CB936104) and the 863 National High Technology Research Development Program of China (2007AA021905).
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