182

eadache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011

Pain and the endogenous antinociceptive

neuronal system: physiologic role of oxytocin

Dor e sistema neuronal antinociceptível endógeno: papel fisiológico

da ocitocina

ABSTRACTABSTRACT

ABSTRACT

The unpleasant pain sensation is a sub-modality of somatic

sensation that exerts fundamental warning and protective

functions. Pain is the more frequent complain in a neurological

outpatient clinic. In a series of 200 consecutive patients in a

neurological outpatient clinic, 51% of them complained of

some type of pain, the more frequents were headache and

carpal tunnel syndrome. The role of oxytocin in pain regulation

was reviewed. It seems that oxytocin may play a major role in

the mechanism of pain regulation, particularly through the

endogenous antinociceptive neuronal system.

eywords: eywords:

eywords: Pain; Headache; Oxytocin; Carpal tunnel syndrome

RESUMORESUMO

RESUMO

A sensação desagradável de dor é uma modalidade sensitivo-

somática que serve como alarme e exerce funções de proteção.

A dor foi a queixa mais frequente em um ambulatório neuro-

lógico. Em uma série de 200 pacientes consecutivos em um

ambulatório de neurologia, 51% deles se queixaram de algum

tipo de dor, mais frequentemente cefaleia e síndrome do túnel

do carpo. O papel da ocitocina na regulação da dor foi

revisado. Parece que a oxitocina pode desempenhar uma

função importante no mecanismo de regulação da dor,

particularmente através do sistema neuronal antinociceptivo.

alavrasalavras

alavras

chave:chave:

chave: Dor; Cefaleia; Ocitocina; Síndrome do

túnel do carpo

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Marcelo Moraes Valença

, Luciana Patrízia A. Andrade-Valença

1,2

, José Antunes-Rodrigues

Neurology and Neurosurgery Unit, Department of Neuropsychiatry, CCS,

Universidade Federal de Pernambuco, Recife, PE, Brazil

Division of Neurology, Universidade de Pernambuco, Recife, Brazil

Department of Physiology, School of Medicine of Ribeirão Preto, Universidade de São Paulo,

Ribeirão Preto, SP, Brazil

Valença MM, Andrade-Valença LP, Antunes-Rodrigues J

Pain and the endogenous antinociceptive neuronal system: physiologic role of oxytocin.

Headache Medicine. 2011;2(4):182-6

INTRODUCTION

The unpleasant pain sensation (pricking, aching,

burning, stinging, or soreness) is a sub-modality of somatic

sensation that exerts fundamental warning and protective

functions.

Under physiologic conditions, pain sensation are

mediated by two primary afferent neurons: 1) the small-

diameter nonmyelinated C-fibers and 2) thinly myelinated

Aδ-fibers, both referred to as nociceptors. Nociceptors

respond to mechanical, thermal, and chemical forms of

energy. Polymodal nociceptors are activated by thermal,

chemical and high-intensity mechanical stimuli. The Aδ

fibers are glutamatergic neurons that transmitter the fast

sharp pain (5-30 m/s). The C-fibers transmitter the slow

dull pain. Substance P is released from C fibers, and may

enhance and prolong the actions of glutamate.

(1)

In human, rapid immersion of a finger in a hot water

bath (57° C) causes at onset a stinging pain after a time

interval of 0.84 s on average. This is followed by a second

wave of a burning pain after 2.1 s. The latency between

the two forms of pain waves decrease as the stimulus moves

up the limbs toward the trunk, and at the trunk level it is

not feasible to obtain a double pain sequence. This double

pain experience is triggered by fast rising stimulus (electric

Headache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011 183

shock, pinprick, or heating pulse). Interestingly, opioid

substances appear to affect the second pain component

more than the first one.

(2,3)

On the other hand, the first

pain is differentially blocked by compression-ischemia.

(1)

FREQUENCY OF PAIN COMPLAINS IN

CLINICAL PRACTICES

Pain is the more frequent complain in a neurological

outpatient clinic. Table 1 illustrates the principal diagnoses

identified in a series of 200 consecutive patients in a

neurological outpatient clinic of one of the authors (MMV,

Hospital Santa Helena, 1993).

the latency, although it reduced the analgesia induced by

OT (1 mg kg

-1

On the contrary, Xu and Wiesenfeld

(8)

interpreted the

increase in the latency response in the hot-plate test in rats

as a result of sedative and vasoconstrictive effects of OT,

rather that an analgesic phenomenon. Additionally, they

also reported that OT-ANT (1 mg/kg, i.p.) did not influence

response latency to heat pain sensitivity in rats.

Yang

(9)

investigated the actions of OT on the analgesia

in both rat and human being. In humans, acute and

chronic low back pain causes significant change of OT

concentration within CSF and plasma. Oxytocin

administration alleviated low back pain. In rats, OT had

a dose-related analgesic effect. The use of the OT-ANT

[d(CH2)5, Tyr(Me)2, Orn8]-vasotocin and naloxone both

reversed the analgesia induced by OT. Oxytocin also

increased the levels of endogenous opioide peptides

(EOP) (endorphin, encephalin, and dynorphin) in the

spinal cord, whereas OT-ANT caused a decline.

As clinical use, OT, vasopressin and somatostatin were

injected into the cerebral ventricle of a ill cancer patient a

diffuse mesothelioma suffering intractable continuous and

incapacitating thoracic pain. Oxytocin induced a strong

analgesia (by 88%) lasting 77 minutes. Somatostatin-14

reduced pain by 90% for 48 min and arginine vasopressin

reduced pain by 95% for 75 min.

(10)

Furthermore, acupuncture caused changes in OT

content in many regions of rat brain, suggesting that OT

might modulate acupuncture-induced analgesia.

(11)

Liu

(12)

studied the effects of intracerebroventricular (icv)

injections of OT, naloxone, or CCK-8 on electro-

acupuncture (EA) analgesia in rats. They concluded that

the role of OT in EA was not entirely dependent upon the

EOP.

Song and coworkers

(13)

studied the possible

involvement of EOP on OT analgesic actions, by using

icv injection of anti-opioid peptide sera in rats which OT

induced an increase of EA analgesia. Injection of anti-

beta-endorphin serum alone attenuated EA analgesia.

Although, the same antiserum treatment, prior to

intraventricular injection of OT, could not block the

enhancement of EA analgesia by OT. The antidynorphin

A1-13 serum alone could also reduce the EA analgesia

and when the antiserum was given prior to injection of OT

a potentiation of the EA analgesia induced by OT was

found. No effect was observed with the administration of

either anti-methionine enkephalin serum or the anti-leucine

enkephalin. They concluded that the enhancement of EA

analgesia by OT does not depend upon the brain EOP.

OXYTOCIN

In 1982, Berkowitz and Sherman

(4)

reported that

peripheral injection of oxytocin (OT) does not have any

analgesic effects. On the other hand, Caldwell et al.

(5)

demonstrated that intracisternal injection of OT in mice

induced analgesia. Kordower and Bodnar

(6)

showed in

rats that injection of OT into the lateral ventricle also

caused analgesia. Besides, OT levels in plasma and

cerebrospinal fluid (CSF) increased after 30-min exposition

to different non-noxious sensory stimulation, which were

concomitant with the development of analgesia.

(7)

The OT

antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-

oxytocin (1 mg kg

-1

) reversed the prolongation of the

latency observed in the TFT after exposition to such stimuli.

The OT-ANT treatment by itself did not change significantly

PAIN AND THE ENDOGENOUS ANTINOCICEPTIVE NEURONAL SYSTEM: PHYSIOLOGIC ROLE OF OXYTOCIN

184

Headache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011

VALENÇA MM, ANDRADE-VALENÇA LP, ANTUNES-RODRIGUES J

In a review Richard and colleagues

(14)

concluded that

"in no case does OT-induced analgesia appear to be

opiate dependent". Interestingly, they also described that

fragment of the OT molecule, oxytocin-,

(7-9)

can under

certain circumstances act as an opioid antagonist.

Urnäs-Moberg and coworkers

(15)

postulated that low

doses of ethanol could cause anti-nociceptive effects via

an oxytocinergic mechanism. Administration of ethanol

also stimulated the elevation in plasma OT levels and the

use of OT-ANT reduced the increased pain threshold

produced by ethanol. However, Urnäs-Moberg and

colleagues

(15)

made a statement that "opioid mechanisms

do not seem to be involved in the oxytocin induced effects

on pain threshold, since the effects are not blocked by

naloxone (Lundeberg, personal communication)." The

results of the mentioned experiment was not published

neither the doses or the study design, as far as we know.

Looking back the results published by Urnäs-Moberg and

colleagues,

(16)

the latency in the tail flick test in the presence

of OT-ANT was higher with OT, suggesting some degree

of analgesia exerted by OT throw some other receptor

subtype not blocked by the OT-ANT used.

Lundeberg and colleagues

(17)

suggested a central

action of OT since after intrathecal injection of this

neuropeptide (1 µg kg

-1

) induced a delay in the reaction

time in the paw pressure test.

Parturition and vaginal dilatation both cause

enhancement in plasma OT concentration and increase

of the pain threshold, and since during the labour is of

paramount importance the action of OT over the uterus,

provoking increment in muscle contraction, an event which

would trigger pain sensation, it would be logical that the

same peptide would exert a dual physiological function:

analgesia and uterus contraction during labor.

(18)

Under physiologic conditions OT is released from

nerve terminals of the neurophypophisis and median

eminence into the blood, into the cerebrospinal fluid (CSF)

or into specific regions of the CNS. The half-life of plasma

OT is 1-2 min. At CSF OT is present with concentrations

raging from 10 to 50 fmol/ml, which half-life is 28 min.

At a physiologic level the OT present in the sytemic blood

does not penetrete into the CSF or into the brain. The OT

perikarya are presented largely in the magnocellular nuclei,

although fibers are widely distributed in CNS (dorso medial

hypothalamic nucleus, thalamic nuclei, limbic system,

mesencefalic central nucleus, substancia nigra, locus

coeruleus, raphe nucleus, nucleus of the solitary tract, dorsal

motor nucleus of the vagus nerve, and at the spinal cord

ending particularly in layers I, II, and X of the gray matter).

In guinea pigs only 2%-3% of the ip administrated

OT were detected in brain. Hence, the necessity of high

doses of OT, if injected systemically, to induce analgesia,

in the case of considering a central site of action.

(19)

It was

reported that the neurohypophyseal hormones or their

fragments are transported under normal conditions from

blood to brain.

Lesions of the PVN had no effect on nociception. In

the spinal cord the OT fibers may originate from PVN

and C-fibers of the dorsal root ganglia.

Modification of the response latencies to the jump

test (hot plate) and TFT at different temperatures were

encountered with OT anti-serum icv injections: no

changes at high temperatures, decrease in the latencies

at moderate temperature, and increase the latencies at

low temperature (analgesia). Similar results were

observed with other antisera, such as against

vasopressin, met-enkephalin, and beta-endorphin.

Naloxone does not cause pain, but may enhance the

perception of pain.

(20)

Thermal nociceptores are activated by extreme

temperatures (>45º C or <5º C). The mechano- and

heat-responsive C-fibers present heat thresholds raging

from 40º and 50º C in the glabrous and hairy skin of

mammals.

In human heat pain thresholds range from

41º to 49º C.

(21)

In addition, chronic treatment with OT had no effect

on analgesia.

(22)

Analgesia may be caused by different type of stress,

(23)

in some of them the analgesia is mediated by EOP,

(24)

other are unaffected by previous opioid receptor blockade

or through a nonopioid mechanism.

Recent evidence from our Laboratory suggests that

OT leads to an analgesic state, an effect that was

abolished with the blockade of opioid receptor by

naloxone, in mice. This indicated that OT might cause

analgesia throw the involvement of EOP.

(25)

Administration of OT (icv) or antioxytocin serum in

rats modified the pain threshold to electroacupuncture

analgesia, evaluated by potassium iontophoresis induced

tail flick. The OT when injected icv elevated both the pain

threshold and electroacupuncture analgesia. On contrary,

the antiserum reduced the analgesia induced by

electroacupuncture.

(26)

The concentration of OT in CSF of dog with spinal

cord compression was higher than what found in control

dogs, suggesting that during painful conditions OT is

released into CSF or other CNS sites to attenuate the animal

unpleasant, hurtful situation.

(27)

Headache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011 185

In humans, intrathecal injection of oxytocin is effective

in treating low back pain for up to 5 hours.

(28)

Interestedly,

it was described an enhanced hind paw withdrawal latency

in response to nociceptive heat after OT subcutaneous

administration in rat, an effect also found in the untreated

cage mates of an OT-treated animal. This analgesic action

of OT was canceled in OT-ANT-injected cage mates.

Suggesting that cage mates develop anti-nociception

mediated via olfactory tract, which is induced throw, an

oxytocinergic mechanism.

(29)

HEADACHE AND OXYTOCIN

Phillips and colleagues

(30)

reported that acute

migraine headache attack can be relieved by intravenous

oxytocin. On the other hand, a few authors reported that

there is a lactational headache in the literature attributed

to OT surges in association with the milk-ejection

reflex.

(31,32)

A case of a 26-year-old woman suffering from

brief attacks of headache that happened on every

occasion of nursing was reported by Askmark and

Lundberg.

(32)

However, a case was described when the

apparent headache trigger was breast overfulness, and

not the oxytocin surge, occurring when the infant was

sleeping through the night or after a missed, delayed, or

partial feed. In this case, interestingly, the headaches were

alleviated by putting the baby to the breast (activation of

the milk-ejection reflex).

(33)

CONCLUSION

In conclusion, pain is a frequent complain observed

in a neurological outpatient clinic. In this report, 51% of

the patients complained of some type of pain, the more

frequents were headache and carpal tunnel syndrome.

Oxytocin plays a major role in the mechanism of pain

regulation, particularly through the endogenous

antinociceptive neuronal system.

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Correspondence

Marcelo M. VMarcelo M. V

Marcelo M. V

alença, MDalença, MD

alença, MD

Neurology and Neurosurgery Unit,

Department of Neuropsychiatry,

Universidade Federal de Pernambuco – Cidade Universitária

50670-420 – Recife, PE, Brazil.

Phone: +55 81 99229394; +55 81 34263501;

Fax: +55 81 21268539

mmvalenca@yahoo.com.br

Received: 5/9/2011

Accepted: 4/12/2011

VALENÇA MM, ANDRADE-VALENÇA LP, ANTUNES-RODRIGUES J