Spatial summation of heat pain in males and females

Sex differences in pain sensitivity have been found to vary between considerable and negligible. It has appeared that the pain stimulation method is critical in this context. It was assumed this might be due to the different degrees of spatial summation associated with the different pain stimulus modalities. Hence, sex differences were investigated in spatial summation of heat pain in 20 healthy women and 20 healthy men of similar age. Pain thresholds were assessed by a tracking procedure and responses to supra-threshold pain stimulation by numerical ratings. Heat stimuli were administered by a thermode with contact areas of 1, 3, 6 and 10 cm2. Pain thresholds were significantly higher with smaller areas stimulated than with larger ones. No significant effect of area was found for the ratings of the supra-threshold stimuli, the intensities of which were tailored to the individual pain threshold. Consequently, spatial summation of heat pain appeared to result mainly in a shift of the pain threshold on the ordinate and not a change of slope of the stimulus-response function in the pain range. In neither of the two pain parameters were there any sex differences. Therefore, the present study demonstrated that sex differences in spatial summation of heat pain are unlikely.     

Pain Perception Is Increased in Congenital but Not Late Onset Blindness

There is now ample evidence that blind individuals outperform sighted individuals in various tasks involving the non-visual senses. In line with these results, we recently showed that visual deprivation from birth leads to an increased sensitivity to pain. As many studies have shown that congenitally and late blind individuals show differences in their degree of compensatory plasticity, we here address the question whether late blind individuals also show hypersensitivity to nociceptive stimulation. We therefore compared pain thresholds and responses to supra-threshold nociceptive stimuli in congenitally blind, late blind and normally sighted volunteers. Participants also filled in questionnaires measuring attention and anxiety towards pain in everyday life. Results show that late blind participants have pain thresholds and ratings of supra-threshold heat nociceptive stimuli similar to the normally sighted, whereas congenitally blind participants are hypersensitive to nociceptive thermal stimuli. Furthermore, results of the pain questionnaires did not allow to discriminate late blind from normal sighted participants, whereas congenitally blind individuals had a different pattern of responses. Taken together, these results suggest that enhanced sensitivity to pain following visual deprivation is likely due to neuroplastic changes related to the early loss of vision.     

Anesthesiologists' practice patterns for treatment of postoperative nausea and vomiting in the ambulatory Post Anesthesia Care Unit

Background

Induction of the COX-2 isoenzyme appears to play a major role in the genesis of central sensitization after nociceptive stimulation. This study aimed to investigate the efficacy of a single, oral dose of the specific COX-2 inhibitor-valdecoxib in attenuating the central sensitization – induced secondary hyperalgesia in a heat/capsaicin pain model in healthy volunteers.

Methods

The study was a randomized, double blind, placebo controlled, crossover, single dose efficacy trial using 20 healthy volunteers. Two hours following placebo or 40 mg, PO valdecoxib, participants underwent skin sensitization with heat/capsaicin, as well as supra-threshold pain and re-kindling measurements according to an established, validated pain model. Subjects rated pain intensity and unpleasantness on a visual analog scale and the area of secondary hyperalgesia was serially mapped.

Results

The area of secondary hyperalgesia produced after 40 mg of valdecoxib was no different than that after placebo. Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation.

Conclusion

We demonstrated that a single, oral dose of valdecoxib when does not attenuate secondary hyperalgesia induced by heat/capsaicin in a cutaneous sensitization pain model in healthy volunteers.     

Effect of pulsed electromagnetic field therapy on experimental pain: A double-blind,randomized study in healthy young adults

ABSTRACT

Previous studies suggested that pulsed electromagnetic field (PEMF) therapy can decrease pain. To date, however, it remains difficult to determine whether the analgesic effect observed in patients are attributable to a direct effect of PEMF on pain or to an indirect effect of PEMF on inflammation and healing. In the present study, we used an experimental pain paradigm to evaluate the direct effect of PEMF on pain intensity, pain unpleasantness, and temporal summation of pain. Twenty-four healthy subjects (mean age 22 ± 2 years; 9 males) participated in the experiment. Both real and sham PEMF were administered to every participant using a randomized, double-blind, cross-over design. For each visit, PEMF was applied for 10 minutes on the right forearm using a portable device. Experimental pain was evoked before (baseline) and after PEMF with a 9 cm² Pelletier-type thermode, applied on the right forearm (120 s stimulation; temperature individually adjusted to produce moderate baseline pain). Pain intensity and unpleasantness were evaluated using a 0–100 numerical pain rating scale. Temporal summation was evaluated by comparing pain intensity ratings obtained at the end of tonic nociceptive stimulation (120 s) with pain intensity ratings obtained after 60 s of stimulation. When compared to baseline, there was no change in pain intensity and unpleasantness following the application of real or sham PEMF. PEMF did not affect temporal summation. The present observations suggest that PEMF does not directly influence heat pain perception in healthy individuals.     

Pavlovian fear memory induced by activation in the anterior cingulate cortex

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA_A receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception.     

Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system

Animal experiments have shown that the nociceptive reflex can be used as an indicator of central temporal integration in the nociceptive system. The aim of the present study on humans was to investigate whether the nociceptive reflex, evoked by repetitive strong electrical sural nerve stimuli, increased when summation was reported by the volunteers. The reflexes were recorded from the biceps femoris and rectus femoris muscles in eight volunteers following a series of stimulations at 0.1, 1, 2, and 3 Hz. Each series consisted of five consecutive stimuli. Using 0.1- and 1-Hz stimulation, the reflex was not facilitated in the course of the five consecutive stimuli. Following 2- and 3-Hz stimulation, the reflex size (root mean square amplitude) increased significantly during the course of the fifth stimulus. This reflex facilitation was followed by a significant increase (summation) in the pain magnitude when compared with 1- and 0.1-Hz stimulation. Furthermore, the threshold for psychophysical summation could be determined. This threshold (stimulus intensity) decreased when the stimulus frequency (1–5 Hz) of the five consecutive stimuli was increased. The nociceptive reflex and the psychophysical summation threshold might be used to clarify and quantify aspects of temporal summation within the human nociceptive system.     

Postnatal Temporal,Spatial and Modality Tuning of Nociceptive Cutaneous Flexion Reflexes in Human Infants

Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8–17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.     

Convergence of nociceptive information from temporomandibular joint and tooth pulp afferents on C1 spinal neurons in the rat

The aim of the present study was to test the hypothesis that there is a convergence of afferent inputs from the temporomandibular joint (TMJ) on C1 spinal neurons responding to electrical stimulation of the tooth pulp (TP). In 14 pentobarbital anesthetized rats, the extracellular single unit activity of 31 C1 spinal neurons and the amplitude in a digastric muscle electromyogram (n = 31) increased proportionally during 1.0-3.5 times the threshold for the jaw-opening reflex (JOR). Of 31 C1 spinal neurons responsive to TP afferents, 28 (approximately 90%) were also excited by electrical stimulation of the ipsilateral TMJ capsule. All neurons tested were divided into three categories of nociceptive specific, wide dynamic range and non-responsive as to their responsiveness to mechanical stimuli (pin prick and touch) of the somatic receptive field (skin of the face, neck, jaw and upper forearm) and TMJ capsule. Nineteen (68%) of 28 C1 spinal neurons received nociceptive information from C fibers of the TMJ capsule. These results suggest that there is a convergence of noxious information from the TMJ and TP afferents on the same C1 spinal neurons, which importantly contribute to pain perception from the TMJ region.     

Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats

Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.     

Intrathecal cholecystokinin interacts with morphine but not substance P in modulating the nociceptive flexion reflex in the rat

The effect of intrathecal (IT) cholecystokinin (CCK), substance P (SP) and morphine (MO) on spinal cord excitability was studied in decerebrate, spinalized rats. CCK had a weaker facilitatory effect on the nociceptive flexion reflex than SP. The possible functional significance of the coexistence of CCK and SP in neurons projecting to the spinal cord was tested by coadministration of the two peptides. At the doses tested no synergistic interaction on the reflex was found with CCK and SP. IT MO caused a brief enhancement followed by a prolonged depression of the reflex. A high dose of CCK injected prior to MO increased the facilitatory effect and decreased the depressive effect of the opiate on the reflex. The effect of desulfated (D) CCK was similar to CCK but at a higher dose. Naloxone (NAL) had a similar effect as CCK when administered prior to MO. The MO-induced depression of the reflex was readily reversed by NAL, but not by CCK. The results indicate that CCK may prevent the inhibitory effect of MO on spinal cord excitability to nociceptive stimulation, but does not reverse it. CCK may alter the balance of excitation-inhibition between various types of dorsal horn interneurons that are involved in the transmission of nociceptive information.     

Analgesia following electrostimulation of midbrain nuclei of rats with a pain syndrome of spinal origin]

The effect of electrostimulation of the mesencephalic grey matter and of the dorsal nucleus raphe on physiological pain produced by nociceptive stimulation (compression of the tail or the skin on the limb by a clamp) and on pathological pain (the pain syndrome of spinal origin) were studied in experiments on albino rats. Pathological pain was induced by creating a generator of pathologically enhanced excitation in the dorsal horn of the spinal cord by local disturbance of the inhibitory mechanisms with the aid of tetanus toxin. It was shown that electrostimulation of the indicated areas abolished both physiological and pathological pain. A conclusion was drawn that analgesia produced by electrostimulation of certain structure of the brain was connected not only with augmentation of the descending inhibition in the spinal cord as in the case of physiological pain caused by peripheral nociceptive stimulation (as shown by several authors), but also with the block of excitation at the supraspinal level. This mechanism should play a decisive role in analgesia realization in the pain syndrome of central origin, both under experimental and natural conditions.     

Changes in 3H-leucine enkephalin binding in spinal cord of frog after dorsal rhizotomy, cordotomy, transcutaneous stimulation and temperature variations: correlation with nociceptive sensitivity

In the frog spinal cord about 50% of the 3H-leucine enkephalin (3H-LE) binding sites (b.s.) were blocked by an endogenous ligand. Three days after deafferentation and cordotomy the number of free b.s. increased by 44 and 56%, respectively. In spinal frogs the threshold of the flexor reflex responses evoked by nociceptive stimuli decreased. More than 7 days after deafferentation and cordotomy the number of both total and free 3H-LE b.s. decreased, while the threshold of the flexor reflex responses returned to that before spinalization. Transcutaneous electrical stimulation (TES) of the hind limbs (30 Hz, 5 minutes) in frogs spinalized 3 hours earlier increased 3H-LE binding at low intensities of stimulation (0.2 mA) and decreased the threshold of the flexor reflex responses. TES at higher intensities (1.0 mA) decreased 3H-LE binding and increased the threshold. Three days after spinalization TES even at low intensity diminished 3H-LE binding and raised flexor reflex threshold. A decrease in the number of free 3H-LE b.s. was found when the frog body temperature was elevated (from 15 to 24 degrees C) or lowered (from 15 to 1 degrees C) for 14 days and was accompanied by an increase in flexor reflex threshold. The data suggest the existence of an endogenous opioidergic system in the frog spinal cord which has a high degree of tonic activity.     

Modulation of the human nociceptive reflex by cyclic movements

During static conditions the nociceptive reflex is known to vary as a function of, for example, the stimulus position, stimulus intensity, and muscle contraction. The aim of the present human study was to investigate whether the reflex and the corresponding perception of pain are modulated by cyclic movements of the limb involved. Reflexes, evoked by nociceptive electric stimulation of the sural nerve, were recorded from the biceps femoris and the rectus femoris muscles in eight volunteers. Four different experiments were performed to compare the nociceptive reflex and pain score elicited during active isometric/dynamic flexion/extension of the knee joint. The amplitudes of the reflexes were largest for the dynamic conditions. The reflexes, evoked during dynamic extension and isometric contraction of the rectus femoris muscle, had the shortest latencies but the recordings from the biceps femoris muscle were larger than from the rectus femoris muscle. Knee joint angle recordings showed that the largest angle variations occurred for the dynamic conditions and were only marginally disturbed for the isometric conditions. A given stimulus intensity evoked the highest pain intensity during isometric contractions. This indicates that there would seem to be no causal relationship between the size of the nociceptive reflex and the pain intensity.     

Barrels IX-proceedings

The properties of a newly developed tonic heat pain model (THPM), which makes use of pulsating contact heat, were investigated in 18 young men. The most important feature of this model is that repetitive heat pulses with an intensity of 1°C above the individual pain threshold are employed. This approach was used to tailor the tonic pain stimulation to the individual pain sensitivity. In the first of two experiments, the effects of pulse frequencies ranging from 5 to 30 pulses per minute (ppm) on ratings of pain intensity and pain unpleasantness (visual analogue scales) were examined. At all frequencies, both ratings increased steadily over the 5-min test period. Frequencies of 15 ppm or more appeared to enhance pain intensity throughout the test period compared to the lower frequencies, but did not appear to alter pain unpleasantness. This suggests that only pain intensity is influenced by slow temporal summation and that a sort of frequency threshold exists for this kind of summation. In the second experiment, the THPM was compared to a well-established form of tonic pain stimulation, the compressor test (CPT); visual analogue scales were again used, and in addition the McGill Pain Questionnaire was employed. The CPT appeared to produce stronger tonic pain than the THPM. However, as is typical with tonic pain, both tonic pain models induced relatively higher values on the affective pain dimension than on the sensory pain dimension. The time course of pain was dynamic in the CPT, with an increase followed by a plateau phase, at least in those subjects who could tolerate the CPT for more than 60 sec. In contrast, as in the first experiment, the pain ratings in the THPM were characterized by a slow and steady increase over time. Moreover, there was absolutely no indication of a dichotomy between “pain-sensitive” and “pain-tolerant” individuals in the THPM, although such a dichotomy was evident in the CPT. This implies that the distinction between pain-sensitive and pain-tolerant individuals can be made only with the CPT, and that this distinction represents individual differences in peripheral vascular reactions to cold rather than in pain perception. In conclusion, the THPM appears to produce a stable and predictable temporal pattern of tonic pain with a predominant affective component, and to be suitable for application in the majority of individuals without causing undue discomfort.     

Peptide antagonist of delta-opioid receptor attenuates inhibition of spinal nociceptive reflex induced by stimulation of arcuate nucleus of the hypothalamus

In lightly pentobarbital-anesthetized and acutely prepared rats, electrical stimulation within the arcuate nucleus of the hypothalamus (ARH) consistently inhibited the tail-flick responses to noxious heating of the tail. The peptide ICI174864, a delta-opioid receptor antagonist applied intrathecally at the lumbar level at a dose of 1 nmol, markedly attenuated this inhibition without affecting the baseline nociceptive threshold. Normal saline injected by the same approach had no effect on the ARH inhibitory modulation. This is the first report showing an involvement of the delta-opioid receptor in the descending inhibition of spinal nociceptive reflex resulting from ARH stimulation.     

Role of endogenous opiates and extracellular K+ accumulation in the inhibition of frog spinal reflexes by electrical skin stimulation

Electrical skin stimulation of the hind limb (10-100 Hz, 30 s-5 min) at the intensity which leads only to the excitation of low threshold afferents depressed (for 1-30 min) the flexor reflex evoked in spinal frogs by nociceptive stimuli. The inhibition, which lasted for longer than 5 min was blocked by naloxone. Short-term poststimulation effects were associated with an increase of extracellular K+ concentration (delta [K]e) and were not blocked by naloxone. Enkephalins or morphine applied to the spinal cord surface increased the threshold for flexor reflexes while naloxone decrease their threshold. The stimulation was followed by short-term hyperpolarization of primary afferents (PAH; 1-5 min) and by depression of dorsal root potentials (DPRs) which had a similar time course to the delta [K]e, and were not blocked by naloxone. This period was frequently followed by longlasting PAH and enhancement of DRPs (5-30 min), which were abolished by naloxone. Superfusion of the isolated spinal cord with opioids produced PAH and enhanced DRPs evoked by nociceptive stimuli, while naloxone or increase of [K] in Ringer solution depolarized primary afferents and depressed DRPs. It is suggested that the antinociceptive effects of electrical stimulation of low threshold cutaneous afferents in spinal frogs involves at least two mechanisms. The short-term effect may result from delta [K]e, especially at high stimulus strength and is equally effective against noxious and non-noxious stimuli. The longlasting effects selectively affecting nociceptive transmission appear to be produced by endogenous opioids.     

Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene

Background

Variation in the serotonin transporter (5-HTT) gene (SLC6A4) has been shown to influence a wide range of affective processes. Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain. Conditioned pain modulation (CPM) - i.e. ‘pain inhibits pain’ - is impaired in chronic pain states and, reciprocally, aberrations of CPM may predict the development of chronic pain. Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM. Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype, with inferred high or low 5-HTT-expression, were included in a double-blind study. A submaximal-effort tourniquet test was used to provide a standardized degree of conditioning ischemic pain. Individualized noxious heat and pressure pain thresholds (PPTs) were used as subjective test-modalities and the nociceptive flexion reflex (NFR) was used to provide an objective neurophysiological window into spinal processing.

Results

The low, as compared to the high, 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs (p = 0.02) and heat-pain (p = 0.02). The CPM-mediated inhibition of the NFR, gauged by increases in NFR-threshold, did not differ significantly between groups (p = 0.75). Inhibition of PPTs and heat-pain were correlated (Spearman’s rho = 0.35, p = 0.02), whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities.

Conclusions

Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.     

Differences in Behavioral Parameters of Long-Term Pain in Formalin Test at the Period of Sex Maturation in Prenatally Stressed Female and Male Rats

The effect of immobilization of pregnant rats was studied on parameters of the specific biphasic behavioral response (BBR) (patterns of flexion, shaking, licking, duration of the phases and of the interphase interval), of which the first phase characterizes the acute, while the second, he long-term pain in a nociceptive formalin test in the 40-day old female and male off-spring. The following was found: (1) an increase of intensity of patterns of flexion and shaking in the extremity injected with formalin at the second response phase and of the phase duration both in males and in females, (2) an increase of the licking pattern during the second phase and of the phase duration in males. Thus, the prenatal stress produced an increase of the pain sensitivity only at the long-term BBR phase; this increase was revealed in males from the patterns organized at the spinal and supraspinal levels, whereas in females, only at the spinal level. It was concluded that at the period of sex maturation, before the onset of sex maturity, the prenatally stressed males had more expressed damages in the behavioral parameters of the long-term pain in the formalin test, as compared with the prenatally stressed females. The comparative analysis of the response parameters allows suggesting the greater damage in males, then in females, of the inhibition process in the descending inhibitory system modulating nociceptive signals at the spinal cord level.     

Changes in the RIII response of the flexion reflex with painful maneuvers

In the search for reliable indirect indices of pain sensation, interest has recently focused on the nociceptive flexion reflex and late components of the brain evoked potentials. In ten volunteers with sciatica, the nociceptive flexion reflex (RIII) and the late component (N150-P220) of the evoked potentials were recorded, with the subjects at rest and during pain produced by the Lasegue manoeuvre. In recordings with the subjects at rest, both responses were stable. During the Lasegue manoeuvre, the RIII response was markedly suppressed, with a mean reduction in area of 40% (P less than 0.001). In contrast, the amplitude of the N150-P220 components did not change significantly. Our results indicate that, of the two parameters tested, RIII alone is a reliable index for measuring pain sensation.     

The Striatum and Pain Modulation

The aim of this review was to give a general aspect of the sensorial function of the striatum related to pain modulation, which was intensively studied in our laboratory. We analyse the effect of electrical and chemical stimulation of the striatum on the orofacial pain, especially that produced by tooth pulp stimulation of the lower incisors. We demonstrated specific sites within the nucleus which electrical or chemical stimulation produced inhibition of the nociceptive jaw opening reflex. This analgesic action of the striatum was mediated by activation of its dopamine D₂ receptors and transmitted through the indirect pathways of the basal ganglia and the medullary dorsal reticular nucleus (RVM) to the sensorial nuclei of the trigeminal nerve. Its mechanism of action was by inhibition of the nociceptive response of the second order neurons of the nucleus caudalis of the V par.