Supraspinal influences on nociceptive flexion reflex and pain sensation in man

The sensation of pain and the nociceptive flexion reflex of the biceps femoris muscle (RIII, Bi) elicited by electrical stimulation of the ipsilateral sural nerve were studied in human during 4 conditions: (1) a mental task; (2) a stress; (3) during noxious stimulation of the contralateral ulnar nerve; (4) after an intense noxious stimulation of the sural nerve itself. An inhibition of both pain sensation and RIII, Bi was observed in (1), while a facilitation of these parameters was noted in (2). In contrast, no change in RIII, Bi occurred in (3) while the pain sensation was inhibited. In (4), just after the noxious stimulation, there was a marked facilitation of RIII, Bi associated with increased pain sensation. However, 10--12 sec later, the pain sensation returned to its control values, while the RIII, Bi reflex was still facilitated. The latter recovered to its control values 28--30 sec later. These results show the possibility of a dissociation between afferent ascending nociceptive messages and nociceptive motor activity (in 3 and 4). They suggest that supraspinal descending influences can act differently on spinal dorsal horn neurons in the case of pain ascending volleys, and in the case of spinal nociceptive motor activity.     

Comparison of trigeminal and spinal modulation of pain and nociception

Modulation of pain and nociception by noxious counterstimulation, also called "diffuse noxious inhibitory controls" or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately.     

Clinical exploration of nociception with the use of reflexologic techniques]

In the first part of this report a methodology is described which allows an objective and specific exploration of experimental pain in man by using some electrophysiological features of cutaneous reflexes. This method can be summarized as follows: in normal and trained volunteers, we studied simultaneously the recruitment curves of the nociceptive flexion reflex of a knee-flexor muscle (biceps femoris muscle) and that of pain sensation elicited by electrical stimulation of the ipsilateral sural nerve at the ankle. In this procedure, we found that the reflex threshold (Tr) was closely related to that of pain threshold (Tp) around a similar value (10 mA). In the same way, both the threshold of the maximal recruitment of the reflex (Tmr) and that of tolerance to pain (Tpt) were found to be close to 33 mA. These values are reliably reproducible in one subject from one session to the other, and in all subjects with minimal inter-individual variations and without any significant inter-sex difference. These close relationships between Tr and Tp and between Tmr and Tpt respectively constituted the basic ground for the elaboration of the methodology for investigating objectively the human nociceptive reactions. In the second part of the paper, this methodology is applied for studying the spinal mechanisms of morphine analgesia when the drug is given either by intravenous route in normal subjects and in paraplegic patients or administered epidurally in patients with acute postoperative pain. On the one hand, the resulting data strongly validate the model since they show that pain and nociceptive reflex are similarly depressed by morphine in a dose-response fashion. On the other hand, data also show that the spinal level is one of the main important sites of the mechanisms of morphine-induced analgesia since this drug is found to strongly depress selectively the nociceptive transmission directly at the spinal level. Finally, this method is applied for investigating the nociceptive reactions in patients affected either with a pathological lack of pain sensation or, by contrast, in patients complaining of acute or chronic pain from various origins. Since the nociceptive flexion reflex can be considered as a specific and objective physiological correlate of a pain sensation, it can be successfully employed as a useful tool for investigating some aspects of the human nociceptive reactions in both experimental and pathological situations.     

Effects of cutaneous histamine application in patients with sympathetic reflex dystrophy

Thirty-six patients suffering from acute reflex sympathetic dystrophy (RSD) were examined in order to evaluate nociceptive C-fibers. Axon reflex vasodilatation was induced by iontophoresis of histamine and recorded (laser Doppler flux). The strength of concomitant sensation was rated on a visual analogue scale, and the quality was characterized as itching or burning pain. Skin temperature was recorded by infrared thermography. The results were compared with investigations of unaffected limbs of patients and volunteers. The histamine-induced sensation on the symptomatic side was more often burning pain than itching (P < 0.001), and skin temperature was increased on the affected limb (P < 0.001). Axon reflex vasodilatation and the strength of sensations were unaltered. In conclusion, this study rules out a significant deterioration of afferent C-fibers in RSD, but gives evidence of sensitization of nociceptive function. This nociceptive sensitization has to be taken into consideration for effective treatment of RSD. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1389–1395, 1997     

Correlation between pain thresholds and polysynaptic components of blink reflex in essential arterial hypertension

An interaction between pain modulation and arterial pressure control has been proposed on the basis of experimental data in man and animal. Eight hypertensive patients and eight normotensive volunteers were investigated by electrical stimulation of the first trigeminal branch and dental pulp, to evaluate nociceptive sensation and reflex responses. A significant threshold increase of pain sensation and R2, R3 polysynaptic components of the blink reflex, has been found in hypertensive patients.     

Study of pain thresholds by recording flexor reflexes in thalamic syndromes

Both thresholds of nociceptive flexion reflex and pain sensation were studied in 6 normal subjects and in 6 patients with typical thalamic pain. In these patients, on the painful side, these thresholds were found increased (98 p. 100; 89 p. 100 respectively) compared to the normal side. Values obtained in this latter did not significantly differ from those observed in normal subjects. After 8 days of indalpine treatment, the nociceptive reflex threshold was furthered increased in the painful side while the pain threshold was not modified by this drug. In the normal side, changes observed after indalpine were similar to that obtained in normal subjects. All the indalpine-induced modifications were reversed by naloxone in both patients and normals. These results are discussed in the context of the possible mechanisms of thalamic hyperpathia.     

Studies on pain. Effects of morphine on a spinal nociceptive flexion reflex and related pain sensation in man

The nociceptive flexion reflex and the corresponding subjective pain score elicited by sural nerve stimulation were studied in 6 healthy volunteers. A significant correlation was found between the respective recruitment curves of the reflex and of the pain score as a function of stimulus intensity. Consequently, the reflex (Tr) and the pain (Tp) thresholds were found to be almost identical (mean: 10.6 and 10.3 mA, respectively). Similarly, the threshold of the maximal reflex response (Tmr) was very close to that of intolerable pain (Tip): 37.1 and 38.8 mA, respectively. These four parameters were studied before and after intravenous administration of morphine chlorhydrate (0.05, 0.1, 0.2 and 0.3 mg/kg) and subsequent administration of naloxone hydrochloride (0.02 mg/kg; i.v.). While 0.05 mg/kg morphine remained without any effect, higher doses produced an increase in the four thresholds (Tr, Tp, Tmr, Tip). Furthermore, a very significant linear relationship was found between the importance of the increase and the dose of morphine. Morphine also depressed in a dose-dependent fashion, the nociceptive reflexes elicited by a constant stimulation intensity (1.2-1.3 Tr). All these effects were immediately reversed by subsequent naloxone. During all the pharmacological situations, variations in Tr and Tp as well as in Tmr and Tip were found to be very significantly linearly related, indicating a close relationship between the effects of morphine on the nociceptive reflex and on the related pain sensation. These results suggest that, in our model involving a brief 'epicritic' nociceptive stimulus, the mechanisms of morphine-induced analgesia in man can be explained by a depressive effect on the nociceptive transmission directly at a spinal level.     

Interaction of nociceptive and non-nociceptive cutaneous afferents from foot sole in common reflex pathways to tibialis anterior motoneurones in humans

In six healthy subjects, the reflex responses of the tibialis anterior muscle (TA) to stimulation of the cutaneous afferents arising from plantar foot, were studied at rest and during different levels of steady voluntary contraction of the TA. At rest, the threshold of the response and the threshold of subjective pain sensation coincided. The mean latency of this TA nociceptive response was 84.7 ms. Steady voluntary contractions of the TA, which was increased progressively from 3% to 15% of the maximum voluntary contraction, produced a significant and parallel reduction in the threshold and latency of the response: at 15%, the mean latency was about 26 ms shorter than at rest and its threshold was about half (i.e. below the pain threshold). The conduction velocity of the afferents responsible for TA response at rest was within the range of A-δ pain afferents (mean 27.4 m/s), whereas during voluntary contraction it was within the A-β fibre range (mean 45.1 m/s). This suggests that descending command makes the discharge of low-threshold, fast-conducting fibres sufficient for reflex activation of TA motoneurones (MNs). Central delay (about 4 ms) and MN recruitment order (according to the size principle) were found to be the same for both nociceptive and non-nociceptive TA reflex responses. Finally, experiments of spatial summation revealed an interaction between nociceptive and non-nociceptive inputs at a premotoneuronal level. It is therefore proposed that nociceptive and non-nociceptive cutaneous afferents arising from the foot sole use the same short-latency spinal pathway to contact TA MNs and that their relative contribution to its segmental activation is contingent upon descending command.     

Differential effect of supraspinal modulation on the nociceptive withdrawal reflex and pain sensation.

OBJECTIVE: To study whether the nociceptive withdrawal reflex (WR) and pain sensation are differentially affected by supraspinal modulation and to determine the nature of this modulation. METHODS: The WR and pain sensation elicited by electrical stimulation were measured in complete spinal cord injury (SCI) subjects and in intact controls under two different experimental conditions; "facilitation" and "neutral" control. RESULTS: Pain sensation was the same under both conditions, whereas the characteristics of the WR were highly dependent on them. In intact body regions the WR threshold was similar to pain threshold under facilitation but was near pain tolerance in neutral conditions. Furthermore, WR was elicited in 100% of trials under facilitation but only in 57% of trials in neutral conditions. Thresholds of WR in paralyzed regions were significantly higher than in intact regions (p<0.001). The former showed a clear stimulus-response relationship as did pain sensation whereas the WR in intact regions did not. CONCLUSIONS: The WR and pain sensation are differentially affected by supraspinal modulation. The WR is subject to both excitatory and inhibitory influences, depending on the instructions subjects receive. SIGNIFICANCE: The experimental setup and subjects' mental state should be considered when interpreting changes in the WR. Extreme caution should be employed when utilizing reflexive indices as a measure of pain. Verbal report seems a more suitable tool to evaluate pain since it is relatively stable with repeated measurements and in accordance with stimulation intensity.     

Sensory signalling effects of tegaserod in patients with irritable bowel syndrome with constipation.

Tegaserod relieves overall and multiple individual constipation-predominant irritable bowel syndrome (IBS-C) symptoms. However, mechanisms for the relief of abdominal pain/discomfort are not well understood. The effects of tegaserod on rectal sensitivity to distension were measured by the nociceptive flexion RIII reflex, as evidenced by spinal hyperexcitability (i.e. increase or facilitation of the RIII reflex), in IBS-C patients. A randomized, double-blind, placebo-controlled, parallel study was performed in 30 women with IBS-C. The effects of slow ramp rectal distension on the RIII reflex, recorded from the lower limb, were measured before [first experimental day (D1)] and after 7 days [day 8 (D8)] of placebo (n=15) or 6 mg tegaserod bid (n=15). Pressure-volume and sensation-volume relationships were measured during distension, and patients reported their IBS symptoms daily. On D1, rectal distension facilitated the RIII reflex in both treatment groups. On D8 vs D1 these facilitatory effects were significantly lower (P<0.001, analysis of variance) after tegaserod (mean reduction: -30.3+/-11.9%) than placebo (mean reduction: -10.1+/-12.9%). No significant changes in the volume-sensation relationship or differences in compliance were observed with tegaserod or placebo. In conclusion, tegaserod reduces the facilitatory effects of rectal distension on the RIII reflex in women with IBS-C.     

Nociceptive threshold and physical activity.

Previous studies using subjective tools to measure pain have shown that muscle exercise can have analgesic effects in man. The nociceptive leg flexion reflex (or RIII reflex) is a useful objective tool for assessing human pain. In this study, the pain threshold was assessed using the nociceptive flexion reflex in six high-level athletes 1) at rest in comparison with 8 control subjects and 2) after exercise requiring the production of a 200-Watt force over a period of 20 minutes. The nociceptive flexion reflex threshold at rest was found to be spontaneously higher in the athletes than in the controls. Physical activity resulted in a significant increase (+53%) in the threshold of the nociceptive reflex in the athletes. The role of stress-induced analgesia, the reduction in perceived intensity of stimuli during movement, and the release of opioids are discussed.     

Inhibitory effects of heterotopic noxious counter‐stimulation on perception and brain activity related to Aβ‐fibre activation

Heterotopic noxious counter‐stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non‐nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter‐balanced sessions, including non‐nociceptive (selective Aβ‐fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20‐min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0–100 scale, where 0 is no pain and 100 the worst pain imaginable). Non‐nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII‐reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non‐nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak‐to‐peak amplitude at Cz was significantly decreased by HNCS for non‐nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aβ‐fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide‐dynamic‐range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.     

Apomorphine effect on pain threshold in Parkinson's disease: A clinical and positron emission tomography study

Patients with Parkinson's disease (PD) frequently experience pain that could be in part due to central modification of nociception. In this randomized controlled double blind study, we compared the effect of apomorphine versus placebo on pain thresholds and pain‐induced cerebral activity in 25 patients with PD. Subjective pain threshold (using thermal stimulation, thermotest), objective pain threshold (nociceptive flexion reflex), and cerebral activity (HO PET) during noxious and innocuous stimulations were performed. Neither subjective nor objective pain thresholds nor pain activation profile were modified by apomorphine compared with placebo in 25 PD patients. Apomorphine has no effect on pain processing in PD. We suggest that other monoamine systems than dopaminergic system could be involved. © 2010 Movement Disorder Society.     

Effect of chemically activated fine muscle afferents on spinal recurrent inhibition in humans.

OBJECTIVE: To test the hypothesis that 'metabolites released during fatiguing muscle contractions excite group III-IV muscle nociceptive afferents, inhibiting homonymous motoneurones via Renshaw cells,' by recording changes in recurrent inhibition of soleus motoneurones when high-threshold, small-diameter afferents (group III-IV fibres) from the same muscle were tonically activated. METHODS: Experiments were performed in 7 healthy subjects at rest and during weak isometric voluntary contraction of the soleus muscle. Muscle nociceptive afferents were activated by local standardized injection of levo-ascorbic acid. Renshaw cells were orthodromically activated by a conditioning H reflex and the resulting recurrent inhibition of the soleus motoneurones was assessed by a subsequent test H reflex. An additional H reflex of the same size as the test reflex was used to assess motoneurone excitability. RESULTS: At rest, muscle nociceptive stimulation produced transient facilitation of both test H and reference H reflexes. Under weak voluntary contraction, muscle nociceptive stimulation produced long-lasting extra-inhibition and extra-facilitation of the test reflex and reference reflex respectively, the time course of which closely resembled that of the subjective muscle pain curve. CONCLUSIONS: Discharge of putative group III-IV muscle afferents facilitated homonymous recurrent inhibition. The filtering property of recurrent inhibition may contribute to limit motoneurone activity during muscle pain and/or adapt motoneurone firing rate to the modified contractile properties of motor units as muscle fatigue developed.     

Modulation of jaw reflexes induced by noxious stimulation to the muscle in anesthetized rats

Previous studies have shown that jaw reflexes and activity patterns of the jaw muscles were modulated in the presence of jaw muscle pain. However, there is no study comparing the modulatory effects on the jaw reflexes induced by noxious stimulation to the jaw muscle. To clarify this, effects of the application of mustard oil (MO), an inflammatory irritant, into the temporalis (jaw-closing) muscle on (1) jaw-opening reflex evoked by tooth pulp stimulation (TP-evoked JOR) as a nociceptive reflex, (2) jaw-opening reflex evoked by inferior alveolar nerve stimulation as a non-nociceptive reflex and (3) jaw-closing reflex evoked by trigeminal mesencephalic nucleus stimulation as a proprioceptive reflex were investigated in anesthetized rats. The MO application induced suppression of all reflexes, and the effect on the TP-evoked JOR was more prominent than on the other reflexes. To elucidate the involvement of endogenous opioid system for the suppressive effect, a systemic administration of naloxone following the MO application was conducted. The MO-induced suppressive effect on the TP-evoked JOR was reversed by the naloxone administration. The results suggest that noxious stimulation to the jaw muscle modulate jaw reflexes particularly for the nociceptive jaw-opening reflex, and the modulatory effect includes both facilitatory and inhibitory aspects. The results also suggest that pain modulatory systems such as the endogenous opioid system play a crucial role in the suppression of the nociceptive transmissions related to nociceptive reflexes, and in some pathological states, defense reflexes may not be evoked properly.     

Effect of continuous vibration on nociceptive flexor reflexes

The effects of continuous segmental vibration on the biceps femoris (BF) nociceptive flexor reflexes elicited by painful electrical stimulation of the sural nerve at the ankle were investigated in 25 normal subjects. During vibration of 100 Hz frequency, applied either on ipsilateral or contralateral foot skin, the nociceptive BF flexor reflexes increased in amplitude. Marked facilitation was prolonged even 20 minutes after vibration ceased. Pain sensation described by subjects did not change significantly except that radiation of pain was reduced in some cases. The results could not be explained by current views of reflex sensitisation, dishabituation, or the gate control theory.     

Stage‐dependent C‐reflex,pain‐like behavior and opioid analgesia during the induction of chronic arthritis in rats

Chronic arthritis (CA) is a common clinical entity associated with persistent pain and limited response to opioid analgesic therapy. However, it is unknown whether these features of CA change depending on its stage of evolution. To address this, in a well‐established animal model of CA we studied the time course of electromyographic responses to electrical stimulation of C fibers (C‐reflex), pain‐like behavior as a response to mechanical nociceptive stimulation, and the inhibition of both responses by a prototypic opioid analgesic, morphine. To induce CA, rats received a single injection of complete Freund's adjuvant into the ankle joint and the C‐reflex responses to electrical stimuli or the nociceptive response to paw pressure test were studied 2, 4 or 6 weeks later. The C‐reflexes evoked by threshold and supra‐threshold electrical stimulation exhibited progressive increases together with enhancement of the nociceptive behavior to mechanical stimulation during induction of monoarthritis. Notably, while systemic morphine produced antinociceptive effects upon both experimental approaches, the effects were markedly reduced during the early stages of CA but enhanced at later stages. These data indicate that C‐reflex and pain‐like responses evolve in parallel, and are inhibited by morphine in a stage‐dependent manner through the induction of CA. The present results may contribute to explain the enhanced pain response and variable analgesic efficacy of opioids that characterize arthritic pain in humans.     

Contralateral Projection of Anterior Cingulate Cortex Contributes to Mirror-Image Pain

Long-term limb nerve injury often leads to mirror-image pain (MIP), an abnormal pain sensation in the limb contralateral to the injury. Although it is clear that MIP is mediated in part by central nociception processing, the underlying mechanisms remain poorly understood. The anterior cingulate cortex (ACC) is a key brain region that receives relayed peripheral nociceptive information from the contralateral limb. In this study, we induced MIP in male mice, in which a unilateral chronic constrictive injury of the sciatic nerve (CCI) induced a decreased nociceptive threshold in both hind limbs and an increased number of c-Fos-expressing neurons in the ACC both contralateral and ipsilateral to the injured limb. Using viral-mediated projection mapping, we observed that a portion of ACC neurons formed monosynaptic connections with contralateral ACC neurons. Furthermore, the number of cross-callosal projection ACC neurons that exhibited c-Fos signal was increased in MIP-expressing mice, suggesting enhanced transmission between ACC neurons of the two hemispheres. Moreover, selective inhibition of the cross-callosal projection ACC neurons contralateral to the injured limb normalized the nociceptive sensation of the uninjured limb without affecting the increased nociceptive sensation of the injured limb in CCI mice. In contrast, inhibition of the non–cross-callosal projection ACC neurons contralateral to the injury normalized the nociceptive sensation of the injured limb without affecting the MIP exhibited in the uninjured limb. These results reveal a circuit mechanism, namely, the cross-callosal projection of ACC between two hemispheres, that contributes to MIP and possibly other forms of contralateral migration of pain sensation.SIGNIFICANCE STATEMENT Mirror-image pain (MIP) refers to the increased pain sensitivity of the contralateral body part in patients with chronic pain. This pathology requires central processing, yet the mechanisms are less known. Here, we demonstrate that the cross-callosal projection neurons in the anterior cingulate cortex (ACC) contralateral to the injury contribute to MIP exhibited in the uninjured limb, but do not affect nociceptive sensation of the injured limb. In contrast, the non–cross-callosal projection neurons in the ACC contralateral to the injury contribute to nociceptive sensation of the injured limb, but do not affect MIP exhibited in the uninjured limb. Our study depicts a novel cross-callosal projection of ACC that contributes to MIP, providing a central mechanism for MIP in chronic pain state.     

Electrophysiological evidence for a release of endogenous opiates in stress-induced‘Analgesia’ in man

The effects of a repetitive stress induced by anticipation of pain were studied on the following somato-vegetative parameters: monosynaptic reflex (H reflex), nociceptive flexion reflex (RIII reflex), heart rate and respiratory frequency, in normal trained volunteers.A progressive increase in heart rate and in respiratory frequency, as well as a facilitation in H reflex parallel to an inhibition of RIII reflex (threshold increased) were observed in all subjects as a function of repetition of stress during 45 min. At this moment, a double-blind injection of a strong dose of naloxone (4 mg) resulted in a rapid exacerbation in vegetative responses (tachycardia, polypnea) as well as in an increase in the facilitation of the H reflex, whereas the RIII reflex was dramatically facilitated (threshold decreased). In contrast, no significant change in these parameters was observed during placebo (saline) injection compared to a control situation (no injection).These data strongly suggest that endogenous opioids are involved in the phenomenon of stress-induced analgesia in man. Moreover, they show that the release of opiates in these conditions possibly modulates non-specific structures which are known to be activated during stress or emotion.     

Dissociation between pain and the nociceptive blink reflex during psychological arousal.

OBJECTIVE: To investigate the effect of psychological arousal on pain ratings and the R2 component of the electrically evoked blink reflex to a 'pure' noiciceptive stimulus. METHODS: Pain ratings and R2 to a noiciceptive stimulus (pulse width 0.3ms, 2mA, delivered from a concentric electrode attached to the supraorbital region of the forehead) were investigated in 16 healthy participants before and during a serial subtraction task, and in 16 control participants who sat quietly during nociceptive stimulation. RESULTS: Pain ratings decreased whereas R2 amplitude increased during the serial subtraction task. CONCLUSIONS: Supra-spinal rather than spinal mechanisms inhibited pain perception during psychological arousal. Moreover, psychological arousal facilitated the R2 component of the blink reflex to a nociception-specific stimulus. SIGNIFICANCE: Supra-spinal influences need to be considered during clinical evaluation of the trigeminal nociceptive blink reflex.