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Current Pharmaceutical Design, 2015, 21, 000-000 1
1381-6128/15 $58.00+.00 © 2015 Bentham Science Publishers
Oxytocin - A Multifunctional Analgesic for Chronic Deep Tissue Pain
Burel R. Goodin1,2,*, Timothy J. Ness1,2 and Meredith T. Robbins1,2
1University of Alabama at Birmingham, Departments of Psychology and 2Anesthesiology
Abstract: The treatment of chronic pain arising from deep tissues is currently inadequate and there is need for new pharmacological
agents to provide analgesia. The endogenous paracrine hormone/neurotransmitter oxytocin is intimately involved in the modulation of
multiple physiological and psychological functions. Recent experiments have given clear evidence for a role of oxytocin in the modula-
tion of nociception. The present article reviews the existent human and basic science data related to the direct and indirect effects of oxy-
tocin on pain. Due to its analgesic, anxiolytic, antidepressant and other central nervous system effects, there is strong evidence that oxy-
tocin and other drugs acting through the oxytocin receptor could act as multifunctional analgesics with unique therapeutic value.
Keywords: Oxytocin, visceral pain, musculoskeletal pain, nociception, analgesics, anxiolytics.
THE PROBLEM
Pain is a ubiquitous experience among humans as well as many
animal species and is commonly understood to be a normal sensa-
tion triggered in the nervous system as an alert to the possibility of
injury and the need for rest and recuperation. In this instance, the
experien ce of acute pain is adaptive and can be considered an ex-
pected consequen ce of illness, injury, and surgery, which most
often resolves with healing. We have reasonably effective drugs for
this type of pain with opioids and anti-inflammatories forming the
mainstays of therapy. However, the experience of chronic pain is an
entirely different matter. There is apparent p athological activation
of the central nervous system (CNS), such that pain signals keep
firing in the nervous system for weeks, months, even years beyond
the expected period of healing or resolution of the source of pain.
Often it is the case that the experience of chronic pain is not reliably
associated with underlying pathology or disease severity. Therefore,
chronic pain does not appear to serve an instrumental role in pro-
tecting the sufferer or in otherwise promoting adaptation and ad-
justment. For those afflicted and their caregivers, chronic pain all
too commonly exerts deleterious effects on sense of well-being and
quality of life. Further, issues with anxiety and depression often
become more prom inent when they co-occur w ith chronic pain.
Even more unfortunate is th e fact that there are currently a limited
number of drugs with demonstrated long-term effectiveness for
controlling chronic pain. Those drugs that do have proven efficacy
for providing pain relief also frequently produce significant side
effects thereby limiting use.
If chronic pain was an uncommon malady, the limited number
of effective drugs currently available for long-term management
perhaps would be of minimal consequence. Unfortunately, this is
not the case as millions of Americans and people world-wide expe-
rience chronic pain [1]. A review of several epidemiological studies
of chronic pain among adults revealed that prevalence estimates in
the general population ranged from 2% to 40%, with a median of
15% [2-4]. In addition to its human cost, chronic pain is an eco-
nomic burden because it requires medical treatment, complicates
medical treatment for other conditions, and hinders people’s ability
to work and function in society. Using the 2008 Medical Expendi-
ture Panel Survey, Gaskin and colleagues recently showed that th e
total annual costs of chronic pain in the United States ranged from
*Address correspondence to this author at the Departments of Psychology
and Anesthesiology, University of Alabama at Birmingham (UAB), 1300
University Blvd., Campbell Hall, Room 328, Birmingham, AL 35294;
Tel: 205-934-8743; Fax: 205-975-6110; E-mail: bgoodin1@uab.edu
$560 to $635 billion in 2010 [5]. The value of lost productivity due
to chronic pain ranged from $299 to $335 billion. Further, it was
revealed that the annual cost of chronic pain was greater than the
annual costs of heart disease ($309 billion), cancer ($243 billion),
and diabetes ($188 billion). Taken together, these data attest to the
unfortunate reality that many Americans m ay suffer from chronic
pain at some point in their lives, and the resultant economic burden
of chronic pain and its treatment is of significant magnitude.
Chronic pain continues to rep resent a formidable current and ongo-
ing public health crisis. As it relates to the focus of this review, the
most common chronic pain conditions are those associated with
deep tissu e structures such as muscle (e.g. fibromylag ia), the gut
(e.g. irritable bowel syndrome, IBS), the bladder (e.g. interstitial
cystitis/bladder pain syndrome, IC/BPS), other digestive organs
(e.g. chronic pancreatitis), reproductive organs (e.g. dysmenorrhea,
endometriosis, chronic prostatitis), and deep craniofacial structures
(e.g. migraine and other types of headache).
For decades, the field of pain medicine has relied upon the use
of opioids for both acute and chronic pain management [6]. How-
ever, adverse effects related to the long-term use of opioids for
chronic pain can be severe and often lead to inadequate pain relief
and ultimately forced drug discontinuation [7, 8]. Some of the more
effective and commonly used non-opioid medications for chronic
pain are drugs that were initially developed to help control depres-
sion and anxiety. Antidepressants including the tricyclic class of
agents, selective serotonin reuptake inhibitors (SSRIs) and sero-
tonin/norepinephrine reuptake inhibitors (SNRIs) have become
commonly used drugs in the treatment of many chronic pain condi-
tions [9-11]. Other drugs identified serendipitously are the anticon-
vulsant ag ents such as carbamazepine, gabapentin and pregabalin
[12]. Although there are currently multiple different pharmacologi-
cal agents available in the United States for the treatment of chronic
pain, effective and sustained pain relief as well as functional resto-
ration comparable to pre-morbid levels unfortunately is rarely
achieved . New, safe, and effective treatments for chronic pain,
therefore, need to be developed.
OXYTOCIN AS A POTENTIAL SOLUTION
With increased understanding of the neurobiology and patho-
physiology of pain, new drug targets have been emerging, which
may lead to novel therapeutic strategies. Currently, a number of
potential targets including TRPV1, TRPA1, voltage-gated sodium
channels, calcium channels, glutamate receptors, and cannabinoids,
are being studied to determine whether they hold promise for future
treatments, particularly for neuropathic and chronic pain conditions
2 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Goodin et al.
[13-17]. One potentially interesting mechanism of action is that
associated with the endogenous nonapeptide, oxytocin (OXY),
which has recently been recognized as an important mediator of
endogenous analgesia [18-22]. OXY is uniquely multifunctional as
it acts as both a neurotransmitter and as a paracrine hormone to
regulate multiple physiological and CNS functions. Produced pre-
dominantly in the supraoptic and paraventricular nuclei (SON &
PVN respectively) of the hypothalamus, and following secretion
into the blood, OXY is best known for its roles in parturition and
lactation. However, it is intimately involved in normative social and
psychological functions including maternal behaviors, attachment
and affiliation associated with pair bonding, depressive mood, anxi-
ety, memory, appetite, sexual function and stress regulation [e.g.,
23-34]. Clinically, OXY has been used in the treatment of autism
[35], sexual dysfunction [36], migraine [37], schizophrenia [38],
drug addiction [39] and other CNS dysfunctions [40]. Extensive
clinical use in experimental studies has identified few toxicities of
OXY treatment [41] apart from those associated with accidental
overdose [42, 43] or use with co-morbidities such as gastroparesis
[44]. OXY has known CNS actions on deep tissue functions via
spinal actions such as alterations of uterine motility [45] and blad-
der emptying [46].
Peripheral and central actions of oxytocin, although related,
appear to be functionally independent in primates [47]. Oxytociner-
gic neurons of the PVN have axonal projections to the spinal cord
which form synaptic connections with neurons in the dorsal horn,
and recent studies have implicated a role for the hormone as a spi-
nal level neurotransmitter with a particular role in the modulation of
first and second order sensory processing [48]. As this review will
demonstrate, there is a growing line of evidence linking OXY to
nociception and pain in animal and human models. A notable char-
acteristic of OXY is that it is multifunctional in ways that are thera-
peutically beneficial. As noted above, there is evidence linking it to
CNS functions including those modulating anxiety, depression and
reward systems. Due to its multifunctional roles, the effects of
OXY in modulating nociceptive transmission and pain perception
can be explained through both physiological and psychological
mechanisms. It has been suggested that oxytocinergic activity may
be closely linked with the endogenous opioid system. Support for
this notion comes from animal studies which have revealed that
OXY administration into CNS sites such as the periaqueductal grey
results in anti-nociception that can be blocked by the administration
of a mu or kappa opioid antagonist [49-55]. It has been proposed
that OXY is an active mechanism underlying acupuncture-induced
analgesia [56-57]. One plausible psychological mechanism linking
OXY with pain is that OXY decreases pain sensitivity by improv-
ing mood. Indeed, animal and human studies have shown that the
administration of OXY affects mood states by reducing anxiety and
depressive symptoms as well as mitigating stress responses [58-61].
Whether OXY exerts its pain attenuating effects directly or indi-
rectly by improving mood and reducing anxiety remains a topic in
need of additional research. Regardless, the end result appears to be
the same; OXY reduces pain sensitivity [62, 63].
ORGANIZATION OF REVIEW
The primary purpose of this article is to provide a focused and
critical review of the recent advances made to date in the endeavor
to better understand the analgesic properties of OXY as well as its
role in the experience of nociception and pain perception. OXY
may directly impact pain through centrally-mediated effects on
areas of the central nervous system important to the experience of
pain including the limbic system, brainstem, and spinal cord [64].
In addition to any direct pain attenuating effects, it has been sug-
gested that OXY could indirectly influence pain via its documented
anti-depressive and anxiolytic properties [65]. In the first part of
this review we briefly discuss the pharmacology of OXY including
its neurohormonal effects and pharmacokinetics. This will be fol-
lowed by a presentation of literature from human and non-human
animal studies, respectively, highlighting the role of OXY in anal-
gesia and pain. Finally, we conclude by discussing some potential
physiological and psychological mechanisms underlying the anal-
gesic properties of OXY.
PHARMACOLOGY
OXY is an endogenous polypeptide that is produced in magno-
cellular neurons of the SON and PVN of the hypothalamus with
sites of release in the posterior pituitary. OXY is highly homolo-
gous to arginine vasopressin, the other neurohormone released by
the posterior pituitary, differing by only 2 amino acids [66, 67].
OXY, which is only nine peptides long, is synthesized from a pro-
hormone by enzymatic cleavage. The cleavage results in two pep-
tides, OXY and neurophysin. Neurophysin does not seem to have
signaling properties but appears to be important in OXY packaging
and processing in secretory granules [68, 69]. While the majority of
OXY is transported to, and released from, the posterior pituitary
into the blood, significant amounts are transported along axons or
dendrites and released in different parts of the CNS including the
spinal dorsal horn. Specifically, oxytocinergic neurons from the
PVN send axonal projections to the superficial and central laminae
of the spinal cord [69-72], which closely corresponds with OXY
receptor expression as determined by autoradiographic binding [73,
74]. Supraspinal sites appear to be the only sources of OXY in the
spinal cord because neither dorsal horn neurons nor primary affer-
ent neurons express significant levels of OXY [75]. Intravenous
OXY has a short half-life of 1-5 minutes, is metabolized by hepatic
and plasma oxytocinases, and the degradation products are excreted
in the urine. Synthetic oxytocin is used clinically for induction of
labor, control of post-partum hemorrhage, and facilitation of lacta-
tion. Several oxytocin receptor antagonist peptides are currently
available, but none of them are approved for clinical usage. Non-
peptide OXY agonists are currently under development [76].
Only one selective receptor for OXY, known as OXTR, has
been characterized although oxytocin can act via vasopressin recep-
tors at high concentrations [66, 67]. OXTR is a rhodopsin type G-
protein coupled receptor with seven transmembrane regions [76].
Upon ligand binding, the receptor activates Gq/11 and G which
together activate phospholipase C (PLC). PLC then generates dia-
cylglycerol (DAG) and 1, 4, 5-inositol triphosphate (IP3). DAG
activates protein kinase C (PKC) which modulates protein activity
by phosphorylation [77]. IP3 facilitates the release of intracellular
Ca2+ [68, 78] and results in alteration of other cellular structures
such as purinergic receptor channels [79]. OXTR localization has
been performed using immunohistochemistry, in situ hybridization,
and a gene deletion mouse model. Localization in the CNS appears
to be relatively widespread. Interestingly, localization in the spinal
cord is limited to the superficial dorsal horn [68, 74, 76]. As a gen-
eral rule, both OXY and OXTR expression is higher in females at
all CNS sites and can be strongly influenced by steroid hormones
[76]. Oxytocinergic neurons in the PVN are activated by noxious
deep tissue (visceral) stimuli as determined by c-fos expression [80,
81].
ANALGESIC EFFECTS OF OXYTOCIN IN HUMANS
A limited evidence base in humans suggests that OXY has the
potential to modulate somatosensory transmission, particularly pain
perception. This ev idence has been derived from co rrelational stud-
ies that examined plasma concentrations of OXY in relation to pain,
as well as randomized and placebo controlled studies that assessed
the analgesic effects of exogenously administered OXY. Despite
various differences in study methodology and sample heterogene-
ity, research in humans generally suggests that low levels of en-
dogenous OXY may be a component of many chronic pain condi-
tions as well as related to increased pain sen sitivity. Further, the
exogenous administration of OXY seems to decrease pain sensitiv-
ity. At the time this review was written, to the best of our knowl-
Oxytocin and Deep Pain Current Pharmaceutical Design, 2015, Vol. 21, No. 00 3
edge there were five existing studies that examined endogenous
OXY concentrations in blood plasma [82-86], seven studies that
administered exogenous OXY an compared it to placebo [80, 86-
91] and a single case study of OXY administered exogenously for
the management of intractable cancer pain [92].
Endogenous OXY concentrations were found to either be sig-
nificantly lower among patients with a chronic pain condition com-
pared with healthy controls, or associated with enhanced pain sensi-
tivity in all five of the studies that assessed plasma OXY concentra-
tions. For instance, two separate studies found that plasma OXY
concentrations were significantly lower among children experienc-
ing recurrent abdominal pain when compared to pain-free children
matched for age and sex [82, 83]. In a study conducted by Yang
[86], it was revealed that adults with acute and chronic low back
pain possessed significantly lower blood plasma concentrations of
OXY compared to healthy controls. One study indicated that there
was no significant difference in blood plasma concentrations of
OXY between women with fibromyalgia and healthy controls;
however, low concentrations of blood plasma OXY were signifi-
cantly associated with ratings of greater pain, stress, and depression
among the fibromyalgia patients [84]. Finally, in a sample of
healthy women subjected to multiple psychophysical pain testing
modalities, it was revealed that low levels of plasma OXY were
associated with reduced pain tolerance for noxious cold and
ischemic stimuli [85].
The seven studies and the single case study that evaluated the
effects of exogenously administered OXY on pain in humans have
produced somewhat mixed results. Despite this inconsistency, the
majority of these studies have found that exogenous OXY admini-
stration is reliably associated with decreases in pain sensitivity. For
example, one study found that intrathecal OXY administration re-
sulted in a dose-dependent reduction of pain in a placebo-controlled
evaluation of men and women with acute or chronic low back pain
[86]. Another placebo-controlled study found that continuous intra-
venous infusion of OXY at doses equal to or greater than 20
mU/min significantly increased thresholds for colonic distention
pain among adults with irritable bowel syndrome [87]. In an early
study that incorporated the inhalation of low doses of OXY (i.e.,
intranasal administration), a group of pain-free individuals who
randomly received inhaled OXY reported significantly less finger
prick pain compared to the group that inhaled a placebo agent [90].
Likewise, a more recent study found that the intranasal administra-
tion of OXY was significantly related, in a dose-dependent manner,
to reports of decreased headache frequency and pain severity in a
sample of individuals with chronic migraine [80]. Administration of
OXY has also been shown to decrease pain in healthy adults, such
that OXY applied intranasally resulted in increased pain thresholds
for a noxious cold water stimulus when compared to placebo [91].
It has also been reported that intraventricular OXY administration
appreciably lessened intractable thoracic cancer pain in a single
case study involving a terminally ill patient with mesothelioma
[92]. Despite these promising results, two studies reported non-
significant associations between exogenous OXY administration
and pain. In a study of women with refractory constipation con-
ducted by Ohlsson and colleagues, intranasal administration of
OXY did not demonstrate a significant advantage over placebo for
constipation relief. However, further analyses revealed that OXY
administration resulted in a significant reduction in reported ab-
dominal discomfort and a non-significant reduction in reported
abdominal pain [88]. L astly, in a small sample of healthy, pain-free
men, it was found that intranasal administration of OXY was unre-
lated to ratings of pain unpleasantness in response to noxious elec-
trical stimulation [89].
A noteworthy limitation of the few human studies that have
examined OXY in relation to pain is that the peripheral versus cen-
tral effects of OXY cannot be directly compared. This is due to the
different means by which OXY was either assessed or administered
in these studies. For those studies that found significant differences
in peripheral levels of endogenous OXY in blood plasma between
individuals with a pain condition compared to healthy controls, it
remains to be determined whether there are also significant differ-
ences in central (i.e., within the CNS) levels of OXY. Although
peripheral and central release of OXY appears to be coordinated
[93], plasma concentrations of OXY do not always reflect central
concentrations [94, 95]. How differences between peripheral and
central OXY concentrations might be related to pain experiences as
well as chronic pain conditions rem ains an area in need of future
research. Similarly, the studies that have exogenously administered
OXY have done so using methods that delivered the OXY either
peripherally (e.g., intravenous infusion) or centrally (e.g., intrathe-
cal injection). Some routes of administration, such as intranasal
inhalation, have both central (through cribiform plate to base of
brain) and peripheral (through vascular absorption) routes of deliv-
ery. Any potential differences in the experience of pain in humans
that might be related to exogenously stimulating peripheral versus
central OXY receptors have yet to be addressed. Additional studies
are needed to determine whether differences in peripheral versus
central OXY concentrations, as well as peripheral versus central
administration routes, differentially affect the pain experiences of
humans. It is worth noting that intranasal administration has been
found to be particularly useful in experimental studies due to the
relatively non-invasive nature of the drug delivery method [96, 97].
Sufficient numbers of studies have been performed the incorporated
intranasal oxytocin, and accordingly, recommendations for the
standardization of this delivery method have been proposed [98].
EFFECTS OF OXYTOCIN ON MOOD FACTORS IN HU-
MANS
Research supports several candidate psychological mechanisms
mediating the pain relieving effects of OXY, including enhance-
ment of subjective well-being, as well as reduction of anxiety and
depressive mood states. An increasing number of investigations into
the effects of OXY on mood began following an animal study dem-
onstrating that wh en rats w ere treated with OXY, they showed a
decrease in plasma corticosterone levels as well as a decrease in
anxiety behavior in response to stress when compared to treatment
with placebo [61]. Along this line, in a placebo-controlled, double-
blind study of healthy men, OXY administration resulted in in-
creased subjective reporting of calmness, reduced anxiety, and in-
creased feelings of wellness there were corroborated by a concomi-
tant suppression of salivary free cortisol [24]. Additional studies
addressing mood factors have reported that patients with major
depression possess significantly reduced levels of plasma OXY
[99]; and in turn, low levels of plasma OXY have been associated
with greater severity of reported depressive symptoms [100]. OXY
has been shown to act as a potent antidepressant [101], which may
be related to functional interactions between the serotonergic and
oxytocinergic systems. Support for this possibility comes from
animal studies which have demonstrated that administration of
SSRIs produce short-term increases in plasma OXY levels [102],
while OXY infusion has resulted in serotonin release within the
median raphe nucleus [103], a primary site of action for SSRIs. A
final line of evidence relating OXY to mood factors known to be
important for the experience of pain comes from research on alter-
native therapies such as hypnosis and meditation, which are readily
applied to the treatment of chronic pain, and that have been shown
to produce feelings of psychological well-being that are mediated
by OXY [104]. Taken together, the findings relating OXY to im-
proved mood and sense of well-being have important implications
for pain in humans because decreased anxiety and feelings of
psychological well-being have been shown to predict better chronic
pain outcomes [105-107]. Thus, OXY may exert a positive influ-
ence on mood and feelings of well-being that, in turn, predicts de-
creased pain sensitivity and increased ability for adjustment to
chronic pain.
4 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Goodin et al.
OXYTOCIN INHIBITS SOMATIC NOCICEPTION
Analgesic effects of OXY have been demonstrated in multiple
non-human species including rodents, dogs [108, 109], cats [110],
and rabbits [111]. OXY administered systemically or at CNS sites
such as the spinal intrathecal space [112], PAG [53, 54], caudate
nucleus [113], nucleus accumbens [114] and amygdala [115] pro-
duces analgesia in rodents. Specifically, studies examining the ef-
fects of OXY administration have shown rats to be less sensitive to
electrical, thermal, chemical and mechanical pain stimuli [49, 116-
125], and to also have less pain following acute stress [75], acute
inflammation [50, 112, 126-129], tooth pulp stimulation [108, 109,
130] and neuropathic injury [131, 132]. In most cases, this analge-
sia was reversed with OXTR antagonists. Kang and Park [133]
demonstrated poor blood brain barrier permeability of OXY but did
observe analgesic effects of systemically administered OXY in the
tail flick assay. The mechanism by which OXY produces these
effects is much less clearly defined. There is mixed evidence that
suggests some of the OXY effects may be through a vasopressin
receptor mechanism [134] but this has been disputed by others
[135-137]. OXTR knockout mice had heat and mechanical pain
tolerances that were similar to wild-type mice, but the OXTR
knockout mice did demonstrate reduced pain tolerance following
swim and restraint stressors [121]. Opioidergic, cannabinoid-
related, and galanin-related systems have been implicated in central
OXY-related analgesia [49-51, 54, 120, 128, 130, 138]. However,
several studies have failed to observe any effect of naloxone treat-
ment on OXY-related analgesia, and so also proposed non-
opioidergic effects [e.g. 139]. Petersson et al [140] demonstrated
long-lasting analgesic effects of OXY in ovariectomized rats when
given the drug intra-vaginally. Anti-inflammatory effects on both
pain-related responses and paw edema were identified after OXY
treatment in rats that received footpad in jections of carrageenan
[136]. An interesting phenomenon noted by Agren et al [141] was
that subcutaneous OXY injection produced increased hindpaw
withdrawal latencies to nociceptive heat in rats that received the
injection as well as their cage-mates that did not receive an injec-
tion.
Multiple brainstem nuclei have the ability to actively modulate
the processing of sensory information at the level of the spinal cord.
Recently, several reports have demonstrated that the PVN of the
hypothalamus can also exert anti-nociceptive descending control
over dorsal horn spinal neurons [e.g., 142, 143], with lesser support
of a role for the supraoptic nucleus [56, 137]. OXY is the main
neurotransmitter that is produced in the PVN and oxytocinergic
neurons have the appropriate spinal cord connectivity to participate
in the modulation of sensory input [144]. However, the mechanism
by which OXY exerts its antinociceptive effect remains to be fully
elucidated.
It has been suggested that OXY indirectly reduces the activity
of spinal dorsal horn neurons following the application of glutamate
[145]. Previous work has demonstrated that oxytocinergic fibers
from the PVN form axo-dendritic synapses in the superficial lami-
nae of the dorsal horn; however, neither neurons in the dorsal horn
nor primary afferent neurons express OXY [71, 75, 134, 146], yet
both groups express OXTR [147]. Stimulation of the PVN results in
neuronal activation of the superficial dorsal horn [148].
Two different investigations have used whole-cell patch clamp
analysis of spinal cord slices to evaluate the individual superficial
lamina neuronal responses to OXY [75, 148]. Robinson et al. [75]
found that OXY inhibited evoked glutamatergic excitatory post
synaptic potentials. It has been shown that OXY has no effect in
OXY knock-out mice due to a concurrent down-regulation of the
OXTR. In addition, Breton et al. [148] found that all lamina II neu-
rons had both spontaneous inhibitory post synaptic currents (sIPSC)
and spontaneous excitatory post synaptic currents (sEPSC). The
most pronounced effect of OXY was an increase in both the fre-
quency and amplitude of sIPSCs. This effect was blocked by both
tetrodotoxin (TTX) and OXTR antagonists, indicating that this
effect is both presynaptic to dorsal horn neurons and that it is recep-
tor specific. Interestingly, in the presence of TTX, OXY increases
the frequency of glutamatergic mEPSCs in approximately 50% of
superficial lamina neurons. This result is identical to those from
whole cell recordings in superficial lamina cultures [148]. Together,
these results appear to indicate that OXY exerts a widespread pre-
synaptic inhibitory role on dorsal horn neurons, but that it may also
increase glutamatergic activation in a smaller population of neu-
rons. Breton et a l. [148, 149] hypothesized that this glutamatergic
excitatory activity, in a subset of dorsal horn neurons, may repre-
sent an amplification system that leads to the facilitation of the
more widely characterized inhibitory neurons in the superficial
lamina. DeLaTorre et al [150] demonstrated that PVN oxytociner-
gic activity prevented or interrupted long-term potentiation in spinal
dorsal horn neurons.
Several elegant studies have used extracellular single unit re-
cording in the dorsal horn to evaluate the role of OXY on specific
cutaneous inputs. In identified spinothalamic tract neurons, PVN
stimulation decreases activity of wide dynamic range (WDR) neu-
rons to noxious but not innocuous stimuli [151, 152]. A separate
population of dorsal horn neurons without receptor fields, known as
PVN-ON neurons, are normally silent but are activated upon stimu-
lation of the PVN [153]. Dual recording experiments show an in-
verse relationship between activity in PVN-ON neurons and spi-
nothalamic tract neurons [153]. Intrathecal OXTR antagonists and
bicuculline, a GABA-A receptor antagonist, eliminate the WDR
neuronal responses to PVN stimulation [154]. These results indicate
that the dorsal horn neuronal response to PVN stimulation is due to
OXY and that activation of GABAergic systems is necessary in the
process. The authors of these studies hypothesize that descending
PVN neurons synapse on GABAergic interneurons in the dorsal
horn. These GABAergic interneurons are then thought to form in-
hibitory synapses on the afferent terminals of A-delta and C-fibers,
but not A-beta fibers [152].
OXYTOCIN INHIBITS VISCERAL NOCICEPTION
In contrast to the role of OXY in somatic nociceptive modula-
tion, minimal work has been performed evaluating the role of OXY
on dorsal horn neuronal responses to noxious visceral stimulation.
The first published evidence of the anti-nociceptive effect of OXY
on noxious visceral stimulation was initially undertaken following
anecdotal reports that women with a painful bladder syndrome
known as interstitial cystitis experience decreased pain while
breastfeeding [155]. Consistent with this human observation, lactat-
ing rats had decreased visceromotor response to urinary bladder
distention [155]. In addition, rats that received intraperitoneal OXY
also had decreased visceromotor response to urinary bladder disten-
tion and this response was reversed by an OXTR antagonist. Fol-
lowing up on this observation, Engle et al [156] demonstrated in-
hibitory effects of oxytocin administered intrathecally on both vis-
ceromotor reflex responses to urinary bladder distension as well as
dorsal horn neurons that were excited by the same stimulus. Again,
these effects of OXY could be reversed pharmacologically by
OXTR antagonists. Notable was the observation that other dorsal
horn neurons became activated by the OXY administration in a
fashion similar to the PVN-ON neurons noted above [153]. To-
gether these data provide strong evidence that spinally delivered
OXY provides anti-nociception to noxious visceral stimulation.
CONCLUSIONS
Deep tissue chronic pain conditions are of immense clinical
importance because: 1) These conditions are generally associated
with anxiety and depression, and 2) standard drug treatments for
these conditions often do not provide effective analgesia and are
associated with significant side-effect profiles as well as abuse po-
tential. OXY and other agents acting through the OXTR would
Oxytocin and Deep Pain Current Pharmaceutical Design, 2015, Vol. 21, No. 00 5
appear to be ideal candidates for the treatment of deep tissue
chronic pain conditions. Studies in humans have demonstrated pain-
relieving effects of OXY, particularly in experimental measures of
deep tissue sensation (ischemic pain/muscle pain) or in deep tissue
pain disorders (irritable bowel syndrome, migraine). Non-human
animal studies are congruent with these human studies and have
expanded on both the physiology and pharmacology of OXY and
OXTR. Exogenously administered OXY has been demonstrated to
produce minimal toxicity at appropriate doses [157] and more im-
portantly, is multifunctional in its actions. Beneficial effects of
OXY have been noted in studies of anxiety, depression, sexual
dysfunction and drug addiction. Taken together, OXY appears to
have potential benefit for also treating the co-morbidities that ac-
company deep tissue pains, and may even treat some of the prob-
lems produced by more traditional treatments for pain such as
opioids. Preliminary evidence suggests that OXY is a novel analge-
sic worthy of additional study to help better determine its value as a
therapeutic agent. What is currently lacking at this time is OXY
research addressing long-term analgesic efficacy, long-term safety
and toxicity, as well as important assessments related to mecha-
nisms of action. These and other studies exploring novel application
of OXY and OXTR agonists simply await support, creativity and
effort so that our understanding of these agents may be enhanced.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
This review was supported by DOD grant W81XWH-11-1-
0452 (M.T.R.), NIH DK51413 (T.J.N.), and a Future Leaders in
Pain Research Award from the American Pain Society (B.R.G.).
LIST OF ABBREVIATIONS
CNS = Central nervous system
DAG = Diacyl glycerol
EPSP = Excitatory post-synaptic potential
IBS = Irritable bowel syndrome
IC/BPS = Interstitial cystitis/bladder pain syndrome
IP3 = Inositol triphosphate
IPSP = Inhibitory post-synaptic potential
OXY = Oxytocin
OXTR = Oxytocin receptor
PLC = Phospholipase C
PKC = Protein kinase C
PVN = Periventricular nucleus
SNRI = Serotonin-norepinephrine reuptake inhibitors
SSRI = Serotonin specific reuptake inhibitors
SON = Supraoptic nucleus
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Received: July 28, 2014 Accepted: October 21, 2014
