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.     

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.     

A new method to increase nociception specificity of the human blink reflex.

OBJECTIVE: The medullary R2 response of the blink reflex can be elicited by innocuous and noxious stimuli. The purpose of this study was to elicit a nociception specific R2 response with a new surface electrode. METHODS: In 10 healthy subjects the blink reflex was elicited using a standard (10-15 mA) and a new concentric surface electrode type (0.6-1.6 mA) which produces a pin-prick-like pain. RESULTS: After topical local anaesthesia with lignocaine/prilocaine R1 was unchanged, R2 was attenuated by 12% after standard stimulation but was almost abolished (-91%) with the new electrode type. CONCLUSION: Stimulation with low stimulus intensities but electrode-dependent high current density allows preferential depolarization of superficial nociceptive A-delta fibres. This new method is less traumatic than others and is useful in the study of trigeminal nociception.     

Seeing touch and pain in a stranger modulates the cortical responses elicited by somatosensory but not auditory stimulation

Viewing other's pain inhibits the excitability of the motor cortex and also modulates the neural activity elicited by a concomitantly delivered nociceptive somatosensory stimulus. As the neural activity elicited by a transient nociceptive stimulus largely reflects non nociceptive‐specific, multimodal neural processes, here we tested, for the first time, whether the observation of other's pain preferentially affects the brain responses elicited by nociceptive stimulation, or instead similarly modulates those elicited by stimuli belonging to a different sensory modality. Using 58‐channel electroencephalography (EEG), we recorded the cortical responses elicited by laser and auditory stimulation during the observation of videoclips showing either noxious or non‐noxious stimulation of a stranger's hand. We found that the observation of other's pain modulated the cortical activity consisting in an event‐related desynchronization in the β band (β ERD), and elicited by nociceptive laser stimuli, but not by auditory stimuli. Using three different source analysis approaches, we provide converging evidence that such modulation affected neural activity in the contralateral primary sensorimotor cortex. The magnitude of this modulation correlated well with a subjective measure of similarity between the model's hand and the onlooker's representation of the hand. Altogether, these findings demonstrate that the observation of other's pain modulates, in a somatosensory‐specific fashion, the cortical responses elicited by nociceptive stimuli in the sensorimotor cortex contralateral to the stimulated hand. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.     

Modulation of electrically induced pain by paired pulse transcranial magnetic stimulation of the medial frontal cortex.

OBJECTIVE: Aim of this study was to investigate whether paired pulse transcranial magnetic stimulation (ppTMS) applied over the medial frontal cortex (MFC) affects acute Adelta fiber-mediated electrically induced pain. In addition, we investigated whether this effect depends on the time course of the stimulation, on the noxious stimulus intensity or on the ppTMS intensity. METHODS: For painful stimulation, the electrical stimulus for the nociceptive flexion reflex (NFR) was used. PpTMS (ISI: 50 ms) was applied over the medial frontal cortex at different intervals ranging from 0 to 1,000 ms following the previous elicited NFR in 10 healthy volunteers. Three sequences at 3 different NFR stimulus intensities (at NFR threshold, 1.3 x and 1.6 x NFR threshold) with a ppTMS stimulus intensity at 1.2 x resting motor threshold (RMT) and one sequence with elevated ppTMS at 1.6 x RMT stimulus intensity were performed. Pain intensity and pain unpleasantness were assessed by visual analogue scales. RESULTS: Pain ratings differed in dependence of the interstimulus interval between NFR and ppTMS. Post-hoc t-tests revealed an increased verbal pain report within interstimulus intervals from 25 to 75 ms at NFR threshold as well as for 25 ms at 1.3 x NFR threshold when ppTMS was applied at 1.2 x RMT and from 0 to 75 ms at 1.6 x NFR threshold when ppTMS was applied at 1.6 x RMT. CONCLUSIONS: The present data suggest that ppTMS over MFC-applied in a certain time window-can enhance pain perception of acute Adelta fiber-mediated electrically induced pain. We hypothesize that the increase of pain is due to interference between ppTMS and the incoming nociceptive input. Further pain processing might be modulated by direct effects on MFC or indirect effects on anterior cingulate cortex (ACC) or spinal nociception. SIGNIFICANCE: Brain areas involved in cognitive and emotional adaptation to pain can be used, in place of primary motor areas, as cortical targets in TMS trials of experimental or ongoing pain.     

Effect of experimental posterior temporalis muscle pain on human brainstem reflexes.

OBJECTIVE: To study the modulation of jaw-stretch and blink reflexes by experimental posterior temporalis muscle pain. METHODS: Thirty healthy volunteers (15 males, 25.5+/-0.6 years and 15 females, 27.4 +/- 1.2 years) were included. Short-latency stretch reflex responses were evoked in the masseter and temporalis muscles by fast stretches (1 mm displacement, 10 ms ramp time) and the blink reflexes were evoked by painful electrical pulses (0.5 ms duration), delivered by a concentric electrode placed on the left lower forehead close to the supraorbital foramen before, during and 15 min after a period with experimentally induced muscle pain. RESULTS: The normalized peak-to-peak amplitude of the stretch reflex in the painful temporalis was significantly higher during pain in both males and females compared with pre- and post-pain conditions (P < 0.004). The R2 root mean square (RMS) of the blink reflex decreased significantly during muscle pain as compared to the pre-pain (P < 0.03) in both males and females. CONCLUSIONS: The present results indicated that experimental posterior temporalis muscle pain facilitates the jaw-stretch reflex, whereas the nociceptive specific blink reflex is inhibited. SIGNIFICANCE: Present study suggested that these reflexes are suitable models for probing pontine and medullary pain processing.     

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.     

Investigation of threshold and magnitude criteria of the nociceptive blink reflex

ObjectiveThe nociceptive blink reflex is a trigeminofacial brain-stem reflex which is used in pain research to evaluate the modulation of pain processing. To standardize the analysis of the reflex we investigated which electromyographic parameters show the best correlation with subjective pain ratings and should therefore be used for scoring blink reflex magnitude. Furthermore we investigated which parameters show the highest accuracy and reliability to define the blink reflex threshold.MethodsForty-six subjects each received 54 electrical stimuli to the supraorbital nerve at nine different stimulus intensities, which corresponded to pain ratings between 0 and 70 (scale 0–100). Multilevel modeling was performed to determine which electromyographic blink reflex parameter showed the best correlation with subjective pain ratings. To define the blink reflex threshold ROC analyses were performed, comparing different electromyographic blink reflex parameters with the judgment of expert raters for 2500 blink reflex recordings from this study and 1400 from another.ResultsThe baseline-adjusted area under the curve showed the best correlation with subjective pain ratings. Seventy-six percent of the residual variance of the pain ratings could be explained by this parameter. The peak z score showed the highest accuracy in defining the blink reflex threshold and also the highest cut-point stability.ConclusionsWe recommend the baseline-adjusted area under the curve for scoring the magnitude of the nociceptive blink reflex and the peak z score to define the nociceptive blink reflex threshold.SignificanceThe here defined standardized criteria to score blink reflex magnitude and threshold improve the comparability and validity of blink reflex studies.     

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.     

Dispositional empathy modulates vicarious effects of dynamic pain expressions on spinal nociception, facial responses and acute pain

Pain communication is thought to promote automatic vicarious self-protective responses as well as empathic concern towards others' suffering. This duality was recently highlighted in a study showing that highly empathic individuals display increased vicarious facilitation of low-level pain processing (nociceptive flexion reflex, NFR) combined with an unexpected reduced facilitation of self-pain perception (pain ratings) while viewing static pictures evoking pain in others. The present study sought to test further the moderating effects of dispositional empathy on vicarious responses induced by viewing dynamic pain expressions. Twenty-four healthy volunteers viewed 1-s videos showing different levels of pain expression before noxious electric shocks were delivered to the sural nerve. Viewing stronger pain expressions generally increased shock-pain unpleasantness ratings, the amplitude of the NFR, and facial responses (corrugator muscle) to the noxious stimulation. However, self-pain ratings (intensity and unpleasantness) increased less or were reduced following clips of pain expression in individuals scoring higher on the Empathy Quotient. These results suggest that vicarious processes facilitate low-level defensive responses, while the experience of self-pain and the associated negative affect may be partly tuned-down by higher-order empathic processes.     

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.     

Diazepam reduces stress-induced analgesia in humans

The analgesic effects of a repetitive stress induced by anticipation of pain (noxious footshock) were studied on both the threshold of a nociceptive flexion reflex and the corresponding pain sensation after a 4-day-treatment of diazepam vs placebo (cross-over and double-blind study) in normal volunteers. During diazepam, the stressor stimulus produced a weaker depression on both nociceptive reflex and pain sensation than that observed during placebo. Furthermore, the reversal effect by naloxone was much more marked during placebo than during diazepam. These data clearly suggest a possible moderating action of benzodiazepine brain type receptors upon the endogenous opiate systems involved in the phenomenon of stress-induced analgesia in humans.     

Emotional Modulation of Pain and Spinal Nociception in Persons with Severe Insomnia Symptoms

Background

Impaired sleep enhances pain, perhaps by disrupting pain modulation.

Purpose

Given that emotion modulates pain, the present study examined whether emotional modulation of pain and nociception is impaired in persons with severe insomnia symptoms relative to controls.

Methods

Insomnia group (n?=?12) met the International Classification of Diseases, tenth revision symptoms for primary insomnia and controls (n?=?13) reported no sleep impairment. Participants were shown emotionally evocative pictures (mutilation, neutral, and erotica) during which suprathreshold pain stimuli were delivered to evoke pain and the nociceptive flexion reflex (NFR; physiological correlate of spinal nociception).

Results

Emotional responses to pictures were similar in both groups, except that subjective valence/pleasure ratings were blunted in insomnia. Emotional modulation of pain and NFR was observed in controls, but only emotional modulation of NFR was observed in insomnia.

Conclusions

Consistent with previous findings, pain modulation is disrupted in insomnia, which might promote pain. This may stem from disrupted supraspinal circuits not disrupted brain-to-spinal cord circuits.     

Diffuse noxious inhibitory controls in humans: A neurophysiological investigation of a patient with a form of Brown-Séquard syndrome

In normal subjects, the application of heterotopic painful stimuli induces simultaneous and parallel decrease in the sensation of pain and of the spinal nociceptive flexion (R_III) reflex evoked by electrical stimulation of the sural nerve. This inhibition of the R_III reflex is absent in tetraplegic patients with clinically complete spinal cord transections and can be triggered only from the analgesic hand in patients with Wallenberg's syndrome. These findings suggest that the inhibitory phenomena observed in normal subjects are likely to be examples of diffuse noxious inhibitory controls (DNICs), being sustained by a loop involving supraspinal structures, the ascending part of which is localized in the spinoreticular tract. We now report an exceptional case of a patient with Brown-Séquard syndrome due to a 4-year-old spinal cord lesion (left side, T-6 level) produced by a knife-wound in the back. Nociceptive flexion (R_III) reflexes elicited by stimulation of cutaneous afferents in the ulnar and sural nerves were studied in the upper and lower limbs by recording from the biceps brachialis and biceps femoris muscles, respectively. For each limb, the R_III reflex threshold was determined. The reflex was then elicited regularly by stimuli of 1.2 times threshold before, during, and after periods of nociceptive electrical conditioning stimulation (15 mA; 4Hz; 1 min) applied successively to the other three limbs. Inhibitions of around 90% followed by after effects (2–3 min) were observed in all situations except that (1) no inhibition could be obtained when the conditioning stimuli were applied to the lower right limb (contralateral to the spinal lesion) and (2) the R_III reflex in the lower left limb was completely insensitive to any of the conditioning stimuli. These results suggest that in humans (1) the ascending part of the loop subserving DNICs is completely crossed at the spinal level and (2) the descending part is confined to the white matter ipsilateral to the limb being tested.     

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.     

Differential Effects of a Distant Noxious Stimulus on Hindlimb Nociceptive Withdrawal Reflexes in the Rat

Recent studies indicate that the nociceptive withdrawal reflexes to individual muscles are evoked by separate reflex pathways. The present study examines whether nociceptive withdrawal reflexes to different muscles are subject to differential supraspinal control in rats. A distant noxious stimulus was used to activate a bulbospinal system which selectively inhibits 'multireceptive' neurons (i.e. neurons receiving excitatory tactile and nociceptive inputs) in the dorsal horn of the spinal cord. Withdrawal reflexes, recorded with electromyographic techniques in single hindlimb muscles, were evoked by standardized noxious pinch. Thirty-seven rats, anaesthetized with halothane and nitrous oxide, were used. Whereas withdrawal reflexes to the extensor digitorum longus and brevis, tibialis anterior and biceps posterior muscles were strongly inhibited, reflexes to interossei muscles were potentiated during noxious pinch of the nose. Reflexes to peronei muscles were not significantly changed. The effects on the reflexes usually had an onset latency of <0.5 s and outlasted the conditioning stimulation by up to 2 s. The monosynaptic la reflex to the deep peroneal nerve, innervating dorsiflexors of the digits and ankle, was not significantly changed during noxious pinch of the nose. Hence, the inhibitory effects on the hindlimb withdrawal reflexes induced by the conditioning stimulation were presumably exerted on reflex interneurons. It is concluded that nociceptive withdrawal reflexes to different hindlimb muscles are differentially controlled by descending pathways activated by a distant noxious stimulus. The results support our previous conclusion that there are separate nociceptive withdrawal reflex pathways to different hindlimb muscles.     

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.     

Is increased spinal nociception another hallmark for Parkinson’s disease?

Augmented spinal nociception during the “off” phase has been observed early in Parkinson’s disease further increasing with disease duration. To find out whether increased spinal nociception represents a premotor feature, experimental pain sensitivity was assessed in idiopathic REM-sleep behavior disorder (IRBD) patients with or without signs of a neurodegenerative disorder compared to early Parkinson’s disease (ePD) patients and healthy controls (HC). Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in 14 IRBD, 15 ePD patients in the medication-defined “off” state and 27 HC in an explorative cohort study. No significant differences between IRBD and HC were found with regard to spinal nociception (NFR) and experimental pain sensitivity. However, IRBD patient with anosmia and/or abnormal DaTSCAN tended to increased experimental pain sensitivity. In contrast, early PD patients exhibited increased NFR responses compared to HC, and a tendency for increased spinal nociception compared to IRBD patients. Increased spinal nociception may represent an early but not a premotor, non-motor feature of PD. Whether increased pain sensitivity already presents a premotor feature should be assessed in further studies.     

Dorsal column stimulation does not inhibit segmental nociceptive reflexes of hind limbs

Stimulation of the dorsal columns has been shown to inhibit many indices of nociception. We report here that dorsal column stimulation does not inhibit two such nociceptive reflexes in the decerebrate cat: the flexion and the crossed extension reflex. In fact, such stimulation typically facilitates these reflexes. These findings suggest that the use of segmental nociceptive reflexes as models of pain perception may not be wholly appropriate.     

Dorsal raphe stimulation, 5-HT and morphine microiontophoresis effects on noxious and nonnoxious identified neurons in the medial thalamus of the rat

In single cell experiments, the characterization of the responses of medial thalamic neurons to noxious and nonnoxious stimulation was made to examine the effects of two substances involved in pain, morphine and 5-HT, and the action of one pain suppressor mechanism, dorsal raphe stimulation. Single cell activity was recorded in urethane anesthetized rats. Tail pinch and tail immersion in hot water were used as nociceptive stimuli. Skin strokes, air puffs and hair brushing were used as nonnociceptive stimuli. Morphine, 5-HT microiontophoresis and dorsal raphe stimulation were performed in all the recorded units. Fifty-eight percent from 61 medial thalamic recorded units responded both to noxious and nonnoxious stimulation; whereas only 18% and 24.6% of the units responded exclusively to noxious and nonnoxious stimulation, respectively. The noxious responding units were located in the most posterior portions of the medial thalamus. Dorsal raphe stimulation and 5-HT ejection prevented the excitation elicited by noxious input. Morphine ejection prevented both the noxious and nonnoxious input in medial thalamus, in a different population as compared to dorsal raphe stimulation or 5-HT ejection. These findings support the existence of a pain ascending mechanism mediated by an opioid-serotonergic interaction in the medial thalamus of the rat.