Spinal and supraspinal correlates of nociception in man

The objective of this work was to simultaneously measure pain-related spinal and supraspinal physiological responses in humans. The sural nerve compound action potential (CAP), the spinal withdrawal reflex (RIII), the somatosensory evoked potential (SEP) and subjective magnitude ratings were elicited by electrical stimulation of the sural nerve in 10 healthy subjects. The sural nerve CAP was used to normalize the evoking stimulus current and to help identify the peripheral nerve afferent types contributing to the physiological and psychophysical responses. Normalizing stimulus current to a proportion of that which elicited a just maximal sural nerve CAP significantly reduced individual variability in magnitude ratings, the RIII and the SEP. Pain and RIII responses only occurred at stimulus levels that were greater than or equal to 1.5 x that which produced a just maximal sural nerve CAP and both responses were positively related to stimulus intensity above that level. Activity in the large diameter A beta fibers will be saturated at stimulus levels near that which produced a just maximal CAP, which implies that both the pain and RIII responses can be attributed to recruitment of the smaller diameter A delta fibers. Although the amplitudes of the P200 and P300 peaks of the SEP were significantly related to stimulation at noxious levels, both were also affected by stimulation at innocuous levels. This result implies that these peaks receive contributions from both noxious and innocuous somatosensory processes. Clearly, the non-pain-related components of these SEP peaks must be identified and isolated before their potential in measuring supraspinal nociceptive processes can be fully realized.     

Possible startle response contamination of the spinal nociceptive withdrawal reflex.

The objective of this study was to examine the possibility that the spinal nociceptive withdrawal reflex, otherwise known as the RIII reflex, is contaminated by the startle response, which is a non-pain-related supraspinal response. Startle response contamination of the RIII reflex would seriously compromise the RIIIs ability to measure spinal nociceptive processes in man, since a change in the startle response affecting EMG amplitude in the RIII latency range would be erroneously interpreted as a change in a spinal nociceptive process. EMG responses evoked by electrical stimulation of the sural nerve were recorded from the orbicularis oculi, neck, biceps, and biceps femoris muscles in 31 healthy human volunteers. The startle response was elicited under conditions often used to record the RIII reflex. Procedures are described that will completely eliminate the startle response. Comparisons between subjects that did and did not elicit a startle response revealed that the startle does not appear to significantly contaminate the biceps femoris RIII reflex, at least when performing group comparisons. There are, however, situations not dealt with in this study in which the startle might significantly contaminate the RIII reflex, such as patients with pre-existing negative emotional states, experimental procedures that induce fear and/or anxiety, and single case studies. It is important, therefore, that investigators using the RIII reflex be cognizant of the startle response and take appropriate precautions to monitor and if necessary eliminate the startle before attributing a change in the RIII reflex to a spinal nociceptive process.     

Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers

Experimental studies in animals have suggested that a combination of morphine and N-methyl-D-aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 microg/kg/min) or their combination were administered intravenously according to a double-blind, placebo controlled and cross-over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind-up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1Hz (intensity: 20% above threshold). The stimulus-response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind-up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind-up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents.     

Comparative study of perceived pain and nociceptive flexion reflex in man

The purpose of this study was to compare the amplitude of the flexion reflex of the biceps femoris muscle (BF) with the intensity of the painful sensation elicited by a nociceptive stimulation resulting from application of a constant-current either on the sural nerve or on the skin in its distal receptive field. Experiments were carried out on 15 normal volunteers.It was observed that: (1) Stimulation of the sural nerve (either on or through the skin) elicits two different reflex responses in the BF: the first (RII) is of short latency, low threshold and corresponds to a tactile reflex. The second (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex. The threshold of RIII was found to be the threshold of a pain sensation. (2) Stimulation of the skin elicits only a late nociceptive (RIII) response in the BF. The threshold of this response was also found to be that of pain. (3) The thresholds of both pain and RIII were found to be higher for sural nerve stimulation (10 mA) than for cutaneous stimulation (5 mA).It was suggested that the large diameter cutaneous fibers could have an inhibitory effect on both pain and the nociceptive reflex. This was supported by the results obtained during a selective ischemic block of the largest diameter fibers in the sural nerve, when a 10 mA stimulation was applied to the nerve. In this case, a decrease of the RII reflex was observed in BF, together with an increase of both RIII and pain sensation. Functional implications of these results are discussed.     

Indirect effects of intrathecal morphine upon diffuse noxious inhibitory controls (DNICs) in the rat

Diffuse noxious inhibitory controls (DNICs) affect all convergent neurones recorded in the dorsal horn of the spinal cord or the nucleus caudalis of the trigeminal system. They are triggered specifically by heterotopic noxious stimulation. DNICs acting at the trigeminal level were triggered by noxious thermal stimulation of caudal parts of the body, and the effects of intrathecal morphine applied at the coccygeal level were tested. The immersion of the right hind paw or of the tail induced inhibitions on C-fibre responses of trigeminal convergent neurones of 95.8 +/- 2.8% and 93.8 +/- 2.4+ respectively. Intrathecal morphine (15 micrograms; 20 microliters) produced an almost complete blockade of inhibitions triggered from the tail without significantly affecting those triggered from the hind paw. A reversal by systemic naloxone (0.4 mg/kg i.v.) was obtained in all cases. These results indicate that intrathecal morphine induced a segmental depression of nociceptive messages strong enough to prevent the spinal initiation of DNICs. We suggest that the segmental depression of nociceptive transmission induced by morphine led to a consequent blockade of DNICs acting on the whole population of convergent neurones not initially affected by the noxious stimulus. These findings are discussed with regard to the strong analgesic effects of intrathecal morphine observed in both behavioural and clinical studies.     

Study of the effects of various transcutaneous electrical nerve stimulation (TENS) parameters upon the RIII nociceptive and H‐reflexes in humans

Despite over two decades of clinical use, the neurophysiological and anti‐nociceptive effects of transcutaneous electrical nerve stimulation (TENS) have yet to be definitively described. The current study was designed to examine the effect of TENS on the RIII nociceptive reflex elicited in healthy human subjects; the H‐reflex was measured concomitantly to monitor changes in α‐motoneuron excitability. Following approval from the university’s ethical committee, 50 healthy human volunteers (25 male and 25 female) participated in the study. The subjects ranged in age from 18 to 30 years (mean 22, SD 3). Subjects were randomly allocated equally to a control group or one of four TENS groups. In the TENS groups, stimulation was applied for a total of 15 min over the sural nerve in the left leg. Ipsilateral RIII and H‐reflexes were recorded five times during the 45 min experimental period. In addition, subjects also rated pain associated with the RIII reflex using a computerized visual analogue scale (VAS). Statistical analysis using two‐way repeated‐measures ANOVA showed no differences between groups for H‐reflex, RIII reflex nor VAS data. These results suggest that TENS does not significantly affect either of the two reflexes, at least using the parameters and application time in the current study.     

Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients

The aim of this study was to evaluate the function of pain modulating systems subserving diffuse noxious inhibitory controls (DNICs) in primary headaches. DNICs were examined in 24 migraineurs, 17 patients with chronic tension-type headache (CTTH) and 20 healthy subjects by means of nociceptive flexion RIII reflex and the cold pressor test (CPT) as heterotopic noxious conditioning stimulation (HNCS). The subjective pain thresholds (Tp) and the RIII reflex threshold (Tr) were significantly lower in CTTH vs. controls. In controls a significant inhibition of the RIII reflex was observed during the CPT (-30%, P < 0.05). Conversely, migraine and CTTH patients showed facilitation (+31%, P < 0.05 and +40%, P < 0.01, respectively) of the RIII reflex during the HNCS. This study demonstrates a dysfunction in systems subserving DNICs in both migraine and CTTH. Impairment of endogenous supraspinal pain modulation systems may contribute to the development and/or maintenance of central sensitization in primary headaches.     

Intracerebroventricular morphine decreases descending inhibitions acting on lumbar dorsal horn neuronal activities related to pain in the rat

Recordings were made from convergent neurons in the lumbar dorsal horn of the rat. These neurons were activated by both innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hindpaw. Transcutaneous application of suprathreshold 2-msec square-wave pulses to the center of the receptive field resulted in responses to A- and C-fiber activation being observed: 27.2 +/- 2.2 (mean +/- S.E.M.) C-fiber latency spikes were evoked per stimulus. This type of response was inhibited by applying noxious conditioning stimuli to heterotopic areas of the body; in particular, immersing the tail in a 52 degrees C waterbath caused a 74.2 +/- 2.0% inhibition of the C-fiber evoked responses; such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC). The effects of microinjections of morphine (0.6-40 micrograms; 2 microliter) within the 3rd ventricle on both the unconditioned C-fiber-evoked responses and the inhibitory processes triggered from the tail were investigated in an attempt to answer two questions: 1) does i.c.v. morphine increase tonic descending inhibitory processes? and 2) what are the effects of i.c.v. morphine on descending inhibitory processes triggered phasically by noxious stimuli? The predominant effect of i.c.v. morphine on the C-fiber-evoked responses was a facilitation (17 of 26 cases). Such a facilitation was dose-related in the 0.6 to 40 microgram range and naloxone reversible; it plateaued from 20 min after the microinjection. No clear relationship was found between the number of C-fiber evoked responses in the control sequences and the subsequent effect of i.c.v. morphine. Intracerebroventricular morphine clearly reduced DNIC in the majority of cases (21 of 26). Such a reduction was dose-related in the 0.6 to 2.5 microgram range and naloxone reversible; it plateaued within 90 min of microinjection. No clear relationship was found between the changes in DNIC and either the number of C-fiber-evoked spikes in the control sequences or the changes in the C-fiber responses induced by i.c.v. morphine. Autoradiographic controls using [3H]morphine showed a labeling along the ventricle wall including the hypothalamus, the periaqueductal gray matter and the floor of the 4th ventricle, three regions which have been implicated in the control of nociceptive transmission at the spinal level. Diffusion from the ventricle wall was over a distance of 0.5 mm and was identical whether observed 20 or 95 min after the microinjections.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prolonged potentiation of transmission through a withdrawal reflex pathway after noxious stimulation of the heel in the rabbit.

The sural-gastrocnemius reflex of the spinalized rabbit was potentiated to an average of 3-6 times control levels after the application of noxious mechanical, thermal or chemical stimuli to the skin of the heel. Facilitation of the reflex was maximal within 1 min of the noxious stimulus, and in many cases persisted for more than 1 h. Prolonged increases in the excitability of the sural-gastrocnemius reflex were not seen after innocuous mechanical or thermal stimulation of the heel. Repetitive electrical stimulation of the sural nerve (100 shocks given at 0.5 Hz) caused persistent facilitation of the reflex when small myelinated A delta fibres or non-myelinated C-fibres were recruited by the conditioning stimulus. Such protracted increases in the excitability of the sural-gastrocnemius pathway would enhance the protective functions of this reflex. The mechanisms described here have probably evolved to provide a high level of reflex protection to the heel after tissue damage has occurred at that site.     

Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings

Aiming at developing a new, noninvasive approach to spinal cord neuromodulation, we evaluated whether transcutaneous direct current (DC) stimulation induces long-lasting changes in the central pain pathways in human beings. A double-blind crossover design was used to investigate the effects of anodal direct current (2 mA, 15 min) applied on the skin overlying the thoracic spinal cord on the lower-limb flexion reflex in a group of 11 healthy volunteers. To investigate whether transcutaneous spinal cord DC stimulation (tsDCS) acts indirectly on the nociceptive reflex by modulating excitability in mono-oligosynaptic segmental reflex pathways, we also evaluated the H-reflex size from soleus muscle after tibial nerve stimulation. In our healthy subjects, anodal thoracic tsDCS reduced the total lower-limb flexion reflex area by 40.25% immediately after stimulation (T0) and by 46.9% 30 min after stimulation offset (T30). When we analyzed the 2 lower-limb flexion reflex components (RII tactile and RIII nociceptive) separately, we found that anodal tsDCS induced a significant reduction in RIII area with a slight but not significant effect on RII area. After anodal tsDCS, the RIII area decreased by 27% at T0 and by 28% at T30. Both sham and active tsDCS left all the tested H-reflex variables unchanged. None of our subjects reported adverse effects after active stimulation. These results suggest that tsDCS holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain.     

A controlled study on the effects of transcutaneous electrical nerve stimulation and interferential therapy upon the RIII nociceptive and H-reflexes in humans

OBJECTIVE: To study the effect of transcutaneous electrical nerve stimulation (TENS) and interferential therapy (IFT) upon the RIII nociceptive reflex and H-reflex. DESIGN: Double-blind conditions. PARTICIPANTS: Seventy healthy subjects were randomly allocated to one of seven groups (n = 10 per group): Control, TENS 1 (5 Hz), TENS 2 (100 Hz), TENS 3 (200 Hz), IFT 1 (5 Hz), IFT 2 (100 Hz), IFT 3 (200 Hz). INTERVENTION: In the treatment groups, stimulation was applied over the right sural nerve for 15 minutes. MAIN OUTCOME MEASURES: Ipsilateral RIII and H-reflexes were recorded before treatment, immediately after treatment, and subsequently at 25, 35, and 45 minutes. Subjects rated the pain associated with the RIII reflex using a computerized visual analogue scale (VAS). RESULTS: Statistical analysis using ANOVA showed no significant differences between baseline and posttreatment measurement for RIII reflex, H-reflex, or VAS data. CONCLUSION: These results suggest that neither type of electrical stimulation (TENS or IFT) affects the RIII or H-reflexes, at least using the parameters and application time in this study.     

Suppression of a hind limb flexion withdrawal reflex by microinjection of glutamate or morphine into the periaqueductal gray in the rat

Microinjection into the midbrain periaqueductal gray (PAG) or lateral reticular formation (LRF) of the neuronal excitant glutamate produces analgesia, and suppresses the responses of a fraction of spinal dorsal horn neurons to noxious heat applied to ventral hind paw skin. Microinjection of morphine into the PAG also produces analgesia, but has been reported to frequently facilitate, as well as to suppress or have no effect, on nociceptive spinal neurons. In anesthetized rats, we tested whether (a) glutamate microinjections into PAG or LRF, and (b) morphine microinjections into PAG, affected the isometric force of hind limb withdrawal elicited by the same noxious heat stimuli on the hind paw as used in single-unit studies of dorsal horn neurons. Glutamate (0.5 M; 0.1-0.5 microliter) microinjected at 9/12 PAG and 8/10 LRF sites suppressed the reflex, and had no effect or facilitated the reflex from the remaining sites. Morphine (5 micrograms in 0.5 microliter) microinjected at each of 10 PAG sites suppressed the reflex in a naloxone-reversible manner. Suppression usually began shortly after morphine, peaked at 20-40 min, and lasted greater than 60 min. The integrated flexion reflex thus appears to be more susceptible to chemical midbrain stimulation under these experimental conditions, compared to previous studies of single dorsal horn neurons.     

Top-down attentional modulation of analgesia induced by heterotopic noxious counterstimulation

Heterotopic noxious counterstimulation (HNCS) by the application of a sustained noxious stimulus has been shown to inhibit nociceptive processes and decrease pain induced by a competing noxious stimulus. However, it is still not clear how attentional processes contribute to these effects. The main objective of this study was to compare the analgesic effects of HNCS in 2 sessions during which top-down attention was manipulated. Acute shock pain and the nociceptive flexion reflex were evoked by transcutaneous electrical stimulations of the right sural nerve in 4 blocks (15 stimuli/block): baseline, heterotopic innocuous counterstimulation (HICS), HNCS, and recovery. Counterstimulation was applied on the left upper limb with a thermode (HICS) or a cold pack (HNCS). Attention was manipulated between sessions by instructing participants to focus their attention on shock pain or counterstimulation. Shock pain ratings decreased significantly during counterstimulation (P<.001) with stronger effects of HNCS vs HICS in both sessions (P<.01). Furthermore, shock pain inhibition during HNCS relative to baseline was stronger with attention focusing on counterstimulation compared to attention focusing on shocks (P = .015). However, the relative decrease in pain ratings during HNCS vs HICS was not significantly affected by the direction of attention (P = .7). As for spinal nociceptive processes, nociceptive flexion reflex amplitude was significantly decreased during counterstimulation (P<.001) with larger reductions during HNCS compared to HICS (P = .03). However, these effects were not altered by attention (P = .35). Together, these results demonstrate that top-down attention and HNCS produce additive analgesic effects. However, attentional modulation of HNCS analgesia seems to depend on supraspinal processes.     

Inhibitory effects of substantia nigra on impulse transmission from nociceptors.

In precollicularly decerebrated cats immobilized with Flaxedil (2 mg/kg, i.v.), a dopamine mechanism played a role in the inhibition produced by brain stem stimulation of nociceptive activated cells in the spinal cord. Lamina V cell activity evoked by natural stimulation (pinch not touch) to the left hind limb or electrical stimulation (0.1 msec pulses at 1/sec) to the left sural nerve exposed at the popliteal fossa was recorded at levels L₆ and L₇. Brain stimulation consisted of 100 msec trains of either single rectangular pulses or 3 pulses/sec for 1 min. The stimulation was delivered to substantia nigra, periaqueductal gray (PAG) and dorsal raphe nucleus via concentric bipolar electrodes. Descending inhibition of the late burst of lamina V cell discharge elicited by mechanical pinch or sural shock could be demonstrated following individual stimulation of the 3 brain stem sites. Nigral-induced inhibition was abolished by injecting tetrabenazine (40 mg/kg, i.v.) or bulbocapnine (20 mg/kg, i.v.); the inhibition was re-established by L-DOPA (20 mg/kg, i.v.) or apomorphine (20 mg/kg, i.v.) indicating that a dopaminergic link has access to the descending inhibitory action on segmental transmission of “pain” impulses. Both nigral and PAG actions were sensitive to methysergide (1 mg/kg, i.v.), while the serotonergic blockade could be overcome by 5-hydroxytryptamine (70 mg/kg, i.v.). We proposed that nigral and PAG actions were relayed in part through the descending raphe system. Through this relay, they exhibit their antinociceptive effects.     

Inhibition of nociceptive neuronal responses in the cat's spinal dorsal horn by electrical stimulation and morphine microinjection in nucleus raphe magnus

The descending inhibitions produced by morphine microinjection and electrical stimulation in the nucleus raphe magnus (NRM) on dorsal horn neurons excited by noxious heating of the skin and/or electrical stimulation of hind limb nerves were examined in the cat. The responses to A-volleys were inhibited to 60.1% (mean, n = 9), those to C-volleys to 64.8% of control (mean, n = 6) and responses to skin heating to 25.3% (mean, n = 8) by electrical NRM stimulation. Morphine (e.g., 10 or 20 micrograms) microinjected into the NRM markedly reduced the responses elicited by afferent C-fiber stimulation (mean 55.6%, n = 8) and the responses to noxious skin heating (mean 38.1%, n = 8), while responses to A-volleys in hind limb nerves were less attenuated (mean 73.6%, n = 8). The effects of morphine were partially or completely blocked by microinjection (10 micrograms) of naloxone into the NRM. It is concluded that morphine microinjection into the NRM generates descending inhibition on the transmission of nociceptive information in the dorsal horn of the spinal cord. This may partly explain the mechanisms of morphine analgesia.     

Prolonged inhibition of primate spinothalamic tract cells by peripheral nerve stimulation

Inhibition of spinothalamic tract (STT) cells was produced by repetitive peripheral nerve conditioning stimulation with high intensity and low frequency pulses. Identified STT cells were recorded from the lumbosacral spinal cord of intact, anesthetized monkeys. In addition, presumed STT cells were recorded from both unanesthetized, decerebrated and decerebrated, spinalized monkeys. These cells were identified by antidromically activating them from the contralateral ventral lateral funiculus of the cervical spinal cord. Both C fiber activity evoked by electrical stimulation of the sural nerve and activity evoked by noxious heat were greatly inhibited by repetitive conditioning stimuli applied either to the common peroneal or tibial nerve with a strong enough intensity for activation of C fibers at 2 Hz for 15 min. The inhibition was maintained during the period of conditioning stimulation and often outlasted stimulation by 20-30 min. The inhibition of cells produced by peripheral nerve stimulation was observed in decerebrate and spinalized animals as well as in intact anesthetized monkeys, although the mean recovery time in the decerebrate group was faster. This indicates that anesthetics did not interfere with the inhibitory mechanism. Furthermore, the presence of inhibition in spinalized animals means the inhibition must depend in part on spinal cord neuronal circuitry. Intravenous injection of naloxone produced a significant but small reduction of the recovery phase of the inhibition. No pharmacological agent was found that substantially interfered with the powerful inhibition produced during peripheral conditioning stimuli. The experimental animal model used in these experiments seems appropriate for studying the mechanisms of analgesia produced by peripheral nerve stimulation.     

Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome

Despite good clinical results, the mechanisms of action of spinal cord stimulation (SCS) for the treatment of chronic refractory neuropathic pain have not yet been elucidated. In the present study, the effects of SCS were assessed on various neurophysiological parameters in a series of 20 patients, successfully treated by SCS for mostly unilateral, drug-resistant lower limb pain due to failed back surgery syndrome. Plantar sympathetic skin response (SSR), F-wave and somatosensory-evoked potentials (P40-SEP) to tibial nerve stimulation, H-reflex of soleus muscle, and nociceptive flexion (RIII) reflex to sural nerve stimulation were recorded at the painful lower limb. The study included two recording sets while SCS was switched ‘ON’ or ‘OFF’ for 1 h. Significant changes in ‘ON’ condition were as follows: SSR amplitude, H-reflex threshold, and RIII-reflex threshold and latency were increased, whereas SSR latency, F-wave latency, H-reflex amplitude, P40-SEP amplitude, and RIII-reflex area were reduced. Analgesia induced by SCS mainly correlated with RIII attenuation, supporting a real analgesic efficacy of the procedure. This study showed that SCS is able to inhibit both nociceptive (RIII-reflex) and non-nociceptive (P40-SEP, H-reflex) myelinated sensory afferents at segmental spinal or supraspinal level, and to increase cholinergic sympathetic skin activities (SSR facilitation). Complex modulating effects can be produced by SCS on various neural circuits, including a broad inhibition of both noxious and innocuous sensory information processing.     

Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: diffuse noxious inhibitory controls in the trigeminal nerve territory.

The purpose of this study was to determine whether the late component of somatosensory evoked potentials (SEP) induced by electrical tooth stimulation and pain intensity are inhibited by heterotopic ischemic stimulation. The tourniquet pressure with 50 mmHg greater than the individual's systolic pressure was applied to the left upper arm for 10 min as ischemic conditioning stimulation. The late component of SEP and visual analogue scale (VAS) were recorded at 4 times and both were significantly decreased when ischemic conditioning stimulation was applied. The maximum reductions in SEP amplitude and the VAS value were 26.1% and 21.2%, respectively, during ischemic conditioning stimulation. After-effect was observed 5 min after removal of the conditioning stimulation. The present study revealed that heterotopic ischemic stimulation attenuated the late component of SEP induced by electrical tooth stimulation, triggering diffuse noxious inhibitory controls (DNIC) and after-effects in the trigeminal nerve territory. It was also suggested that the DNIC effect differs, depending on the intensity, kind, and quality of the test and conditioning stimuli.     

Cannabinoid‐induced effects on the nociceptive system: A neurophysiological study in patients with secondary progressive multiple sclerosis

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients’ electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double‐blind, placebo‐controlled, cross‐over study we investigated cannabinoid‐induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H‐reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta‐9‐tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid‐induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.     

Reduced pain inhibition is associated with reduced cognitive inhibition in healthy aging

The analgesic effect of heterotopic noxious counter-stimulation (HNCS; “pain inhibits pain”) has been shown to decrease in older persons, while some neuropsychological studies have suggested a reduction in cognitive inhibition with normal aging. Taken together, these findings may reflect a generalized reduction in inhibitory processes. The present study assessed whether the decline in the efficacy of pain inhibition processes is associated with decreased cognitive inhibition in older persons. Healthy young (18-46 years old; n = 21) and older (56-75 years old; n = 23) adult volunteers participated in one experimental session to assess the effect of HNCS (cold pain applied on the left forearm) on shock pain and RIII reflex induced by transcutaneous electrical stimulation of the right sural nerve. In the same session, participants also performed a modified Stroop task, including a target condition requiring the frequent switching between inhibition and no inhibition of the meaning of color words. The analgesic effect induced by HCNS was significantly smaller in older participants for both shock-pain ratings (P < 0.001) and RIII-reflex amplitude (P < 0.05). The Stroop effect was significantly larger in elderly participants in the inhibition trials of the switching condition. Increased cognitive interference (ie, larger Stroop effect) correlated with smaller inhibition of the RIII reflex by HNCS across groups (r = −.34, P = 0.025). This association was independent from the age-related slowing observed in control reading and naming tasks. These results suggest a generalized age-related reduction in inhibitory processes affecting both executive functions and cerebrospinal processes involved in the regulation of pain-related responses induced by competing nociceptive threats.