Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides

doi:10.1016/j.peptides.2011.03.007

Peptides

Volume 32, Issue 6, June 2011, Pages 1255-1261

https://doi.org/10.1016/j.peptides.2011.03.007 Get rights and content

Abstract

Periaqueductal gray (PAG) plays a very important role in pain modulation through endogenous opiate peptides including leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek), β-endorphin (β-Ep) and dynorphin A_1–13 (DynA_1–13). Our pervious study has demonstrated that intra-PAG injection of oxytocin (OXT) increases the pain threshold, and local administration of OXT receptor antagonist decreases the pain threshold, in which the antinociceptive role of OXT can be reversed by pre-PAG administration of OXT receptor antagonist. The experiment was designed to investigate the effect of OXT on endogenous opiate peptides in the rat PAG during the pain process. The results showed that (1) the concentrations of OXT, L-Ek, M-Ek and β-Ep, not DynA_1–13 in the PAG perfusion liquid were increased after the pain stimulation; (2) the concentrations of L-Ek, M-Ek and β-Ep, not DynA_1–13 in the PAG perfusion liquid were decreased by the OXT receptor antagonist; (3) the increased pain threshold induced by the OXT was attenuated by naloxone, an opiate receptor antagonist; and (4) the concentrations of L-Ek, M-Ek and β-Ep, not DynA_1–13 in the PAG perfusion liquid were increased by exogenous OXT administration. The data suggested that OXT in the PAG could influence the L-Ek, M-Ek and β-Ep rather than DynA_1–13 to participate in pain modulation, i.e. OXT in the PAG participate in pain modulation by influencing the L-Ek, M-Ek and β-Ep rather than DynA_1–13.

Highlights

► The concentrations of oxytocin (OXT), leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek) and β-endorphin (β-Ep), not dynorphin A_1–13 (DynA_1–13) in the PAG perfusion liquid were increased after the pain stimulation. ► The concentrations of L-Ek, M-Ek and β-Ep, not DynA_1–13 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 DynA_1–13 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 DynA_1–13.

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 A_1–13 (DynA_1–13), 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 DynA_1–13 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 DynA_1–13 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).

References (37)

R. Arletti et al.
Influence of oxytocin on nociception and morphine antinociception
Neuropeptides
(1993)
R.J. Bodnar
Endogenous opiates and behavior: 2009
Peptides
(2010)
Y. Ge et al.
Blockade effect of mu and kappa opioid antagonists on the anti-nociception induced by intra-periaqueductal grey injection of oxytocin in rats
Brain Res
(2002)
M.J. Millan et al.
Vasopressin and oxytocin in the rat spinal cord: distribution and origins in comparison to [Met]enkephalin, dynorphin and related opioids and their irresponsiveness to stimuli modulating neurohypophyseal secretion
Neuroscience
(1984)
M.J. Millan et al.
The endocrinology of the opioids
Int Rev Neurobiol
(1985)
Kh. Reeta et al.
Role of kappa- and delta-opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice
Regul Pept
(2006)
G.J. Rosen et al.
Distribution of oxytocin in the brain of a eusocial rodent
Neuroscience
(2008)
J.P. Rosenfeld
Interacting brain stem components of opiate-activated, descending, pain-inhibitory systems
Neurosci Biobehav Rev
(1994)
H.E. Ross et al.
Characterization of the oxytocin system regulating affiliative behavior in female prairie voles
Neuroscience
(2009)
J.A. Stamford
Descending control of pain
Br J Anaesth
(1995)

D.X. Wang et al.

Arginine vasopressin induces rat caudate nucleus releasing acetylcholine to participate in pain modulation

Peptides

(2010)

J. Yang et al.

Through V2, not V1 receptor relating to endogenous opiate peptides, arginine vasopressin in periaqueductal grey regulates antinociception in the rat

Regul Pept

(2006)

J. Yang et al.

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the caudate nucleus to participate in pain modulation

Peptides

(2011)

J. Yang et al.

Only through the brain nuclei, arginine vasopressin regulates antinociception in the rat

Peptides

(2006)

J. Yang et al.

Central oxytocin enhances antinociception in the rat

Peptides

(2007)

J. Yang et al.

Effect of oxytocin on acupuncture analgesia in the rat

Neuropeptides

(2007)

J. Yang et al.

Effect of arginine vasopressin on acupuncture analgesia in the rat

Peptides

(2009)

J. Yang et al.

Arginine vasopressin enhances periaqueductal grey synthesis and secretion of enkephalin and endorphin in the rat

Brain Res Bull

(2006)

Cited by (50)

Using a birth ball to reduce pain perception in the latent phase of labour: a randomised controlled trial
2024, Women and Birth
Admission in the latent phase of labour is associated with higher rates of obstetric intervention. Women are frequently admitted due to pain. This study aimed to determine whether using a birth ball at home in the latent phase of labour reduces pain perception on admission.
A prospective, pragmatic randomised controlled trial of 294 low risk pregnant women aged 18 and over planning a hospital birth. An animated educational video was offered at 36 weeks’ gestation along with a birth ball. The primary outcome was pain on a Visual Analogue Scale on admission in labour. Participants who experienced a spontaneous labour were invited to respond to an online questionnaire 6 weeks’ postpartum.
There were no differences in the mean pain scores; (6.3 versus 6.5; 90%CI −0.72 to 0.37 p = 0.6) or mean cervical dilatation on admission (4.7 cm versus 5.0 cm; 95% CI −1.1 to 0.5 p = 0.58). More Intervention participants were admitted in active labour (63.6% versus 55.7%; p = 0.28) and experienced an unassisted vaginal birth (70.3% v. 65.8%; p = 0.07) with fewer intrapartum caesarean sections (7.5% v. 17.9%; p = 0.07) although the trial was not powered to detect these differences in secondary outcomes. Most participants found the birth ball helpful (89.2%) and would use it in a future labour (92.5%).
Using the birth ball at home in the latent phase is a safe and acceptable strategy for labouring women to manage their labour, potentially postpone admission and reduce caesarean section. Further research is warranted.
The role of oxytocin, vasopressin, and their receptors at nociceptors in peripheral pain modulation
2021, Frontiers in Neuroendocrinology
Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to be an important phenotype that those two neurohormones strongly downregulate. Nociceptors, the first component of the ascending neural circuit for pain signals, have constantly been shown to be modulated by those peptides. The nociceptor modulation appears to be critical in pain attenuation, which has led to a gradual increase in scientific interest about their physiological processes and also drawn attention to their translational potentials. This review focused on what are recently understood and stay under investigation in the functional modulation of nociceptors by oxytocin and vasopressin. Effort to produce a nociceptor-specific view could help to construct a more systematic picture of the peripheral pain modulation by oxytocin and vasopressin.
Differential role of specific cardiovascular neuropeptides in pain regulation: Relevance to cardiovascular diseases
2020, Neuropeptides
In many instances, the perception of pain is disproportionate to the strength of the algesic stimulus. Excessive or inadequate pain sensation is frequently observed in cardiovascular diseases, especially in coronary ischemia. The mechanisms responsible for individual differences in the perception of cardiovascular pain are not well recognized. Cardiovascular disorders may provoke pain in multiple ways engaging molecules released locally in the heart due to tissue ischemia, inflammation or cellular stress, and through neurogenic and endocrine mechanisms brought into action by hemodynamic disturbances. Cardiovascular neuropeptides, namely angiotensin II (Ang II), angiotensin-(1-7) [Ang-(1-7)], vasopressin, oxytocin, and orexins belong to this group. Although participation of these peptides in the regulation of circulation and pain has been firmly established, their mutual interaction in the regulation of pain in cardiovascular diseases has not been profoundly analyzed. In the present review we discuss the regulation of the release, and mechanisms of the central and systemic actions of these peptides on the cardiovascular system in the context of their central and peripheral nociceptive (Ang II) and antinociceptive [Ang-(1-7), vasopressin, oxytocin, orexins] properties. We also consider the possibility that they may play a significant role in the modulation of pain in cardiovascular diseases. The rationale for focusing attention on these very compounds was based on the following premises (1) cardiovascular disturbances influence the release of these peptides (2) they regulate vascular tone and cardiac function and can influence the intensity of ischemia – the factor initiating pain signals in the cardiovascular system, (3) they differentially modulate nociception through peripheral and central mechanisms, and their effect strongly depends on specific receptors and site of action. Accordingly, an altered release of these peptides and/or pharmacological blockade of their receptors may have a significant but different impact on individual sensation of pain and comfort of an individual patient.
Oxytocin in the periaqueductal gray mainly comes form the hypothalamic supraoptic nucleus to participate in pain modulation
2019, Peptides
Citation Excerpt :
The data might suggest that OXT in SON could be delivered to PAG during pain modulation. OXT enhances PAG synthesis and secretion of leucine-enkephalin, methionine-enkephalin and β-endorphin to participate in pain modulation [31]. Histological study has pointed that there are nerve fiber connections between SON and PAG [32,33], specially the some OXT-ergic fibers in PAG come from SON neurons [18,20–23,34].
Oxytocin (OXT) that effects the nociception process is mainly synthesized and secreted in the hypothalamic supraoptic nucleus (SON). Although the periaqueductal gray (PAG) hardly synthesizes OXT, OXT in PAG also plays a role in pain regulation. The communication investigates whether OXT in the PAG comes from SON to influence pain modulation. RT-PCR was used to analyze OXT mRNA expression and radioimmunoassay to measure OXT concentration. The results showed that (1) pain stimulation enhanced OXT mRNA expression in the SON at 10 min (268.1 ± 39.2%, p < 0.001) and 20 min (135.4±37.9%, p < 0.05) treatment and did not change in the PAG; (2) OXT level increase in SON perfusion liquid during pain stimulation [236.7±22.1% at 10 min (p < 0.001), 223.1±12.4% at 20 min (p<0.001), 56.1 ± 15.7% at 30 min (p < 0.01) and 11.2±14.2% at 40 min] was earlier than that in PAG perfusion liquid [17.8±9.7% at 10 min, 375.6±35.1% at 20 min (p <  0.001), 123.2±17.7% at 30 min (p <  0.001) and 52.7±22.4% at 40 min (p < 0.05)]; (3) SON excitation (L-glutamate sodium microinjection) induced OXT level increase in PAG perfusion liquid in a dose-dependent manner; (4) the bilateral SON cauterization completely controlled and the right SON cauterization partly reversed the pain stimulation induced-OXT concentration increase in PAG perfusion liquid. The data suggested that OXT in PAG came from SON, which might influence the pain process.
Effects of intranasal oxytocin on tactile perception
2019, Neuroscience Letters
In addition to its role in childbirth labor and lactation, oxytocin is a well-known neurohormone, having several prosocial effects. Moreover, oxytocin seems to play a significant modulatory role in painful experiences, due to its participation in central and peripheral processing of nociceptive somatosensory information. Despite studies on oxytocin in pain modulation, there is a scarce literature investigating the role of oxytocin in tactile perception. Here we investigate the effects of 24 and 40 IU intranasal administration of oxytocin in the non-harmful mechanical tactile detection threshold in men. The data showed a significant increase in tactile perception in an experimental 40 IU oxytocin group. We suggest that this effect could be the basis for the oxytocin-bonding effect via touch.
Opioids and the hormone oxytocin
2019, Vitamins and Hormones
The neuropeptide Oxytocin (ΟΤ) is involved as a neurohormone, a neurotransmitter, or a neuromodulator in an extensive range of central and peripheral effects, complex emotional and social human behaviors, memory and learning processes. It is implicated in homeostatic, neuroadaptive processes associated with stress responses and substance use via interactions with the hypothalamic–pituitary–adrenal (HPA) axis and the dopamine mesolimbic reward stress system. This chapter reviews the preclinical and clinical literature on the complicated relationships between endogenous and exogenous opioids and ΟΤ systems and attempts to highlight key findings to date on the effectiveness of intranasal OT administration to treat opioid use disorders. OΤ seems to attenuate, even inhibit, the development of opioid use disorders in preclinical models but is still under clinical research as a promising pharmacological agent in the treatment of opioid use related behaviors. Evidence suggests a role for OT as an adjunctive or stand-alone treatment of behavioral, cognitive and emotional deficits associated with substance use, which may be responsible for seeking behavior and relapse. The mechanisms by which oxytocin acts to reverse the neural substrates of these deficits, partially due to substance induced alterations of the endogenous OT system, and thus modify the behavioral response to substance use are discussed. Other clinically relevant issues are also discussed.

View all citing articles on Scopus

View full text

Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides

Abstract

Highlights

Introduction

Section snippets

Animals

Materials

The concentrations of OXT, L-Ek, M-Ek and β-Ep in the PAG perfusion liquid were increased after the pain stimulation

Discussion

Acknowledgments

Neuropeptides

Peptides

Brain Res

Neuroscience

Int Rev Neurobiol

Regul Pept

Neuroscience

Neurosci Biobehav Rev

Neuroscience

Br J Anaesth

Peptides

Regul Pept

Peptides

Peptides

Peptides

Neuropeptides

Peptides

Brain Res Bull