Facilitation of the tail-flick reflex by noxious cutaneous stimulation in the rat: antagonism by a substance P analogue

Effects of noxious cutaneous stimulation on the tail flick reflex were examined in the anaesthetized rat. Noxious stimulation was applied by immersing the distal 4 cm of the tail in water at 55 degrees C for 1.5 min. The tail flick reflex was tested at 3 min intervals by applying a noxious radiant heat stimulus to a region of the tail 10 cm proximal to the tip. Tail immersion reduced reaction time to tail flick by 30% and 20% at 0.5 and 3.5 min after immersion, respectively. Reaction time returned to control at 6.5 min and tended to increase above baseline values at 9.5 and 12.5 min. Naloxone (10 mg/kg, i.p.) potentiated the effects of tail immersion on reaction time and prevented the increase above baseline. When the surface temperature of the skin used to evoke the tail flick reflex was raised by 10 degrees C using innocuous radiant heat, reaction time was not significantly different from the control, suggesting that an increase in skin temperature per se is insufficient to account for the response to immersion. Intrathecal administration of a substance P antagonist (1 nmol) attenuated the response to tail immersion. These results indicate that noxious cutaneous stimulation may release an agent in the spinal cord which facilitates the tail flick reflex, and that this agent is antagonized by a substance P antagonist.     

The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat

Neurons of the rostral ventromedial medulla (RVM) have been implicated in the modulation of nociceptive transmission. In order to further analyze their role in pain behavior, we studied their activity while eliciting the tail flick reflex with noxious heat. Recording sites were regions in the RVM from which microstimulation (less than or equal to 10 microA, 400 mu sec, 50 Hz continuous pulse trains) inhibited the tail flick reflex. Extracellular unit activity and tail temperature were recorded, stored, and plotted with reference to either the time of tail flick or the time when the stimulating temperature reached 45 degrees C. Neuronal discharges were found to be either increased (on-cells), decreased (off-cells), or unchanged around the time of the tail flick. The decreases in discharge were more closely correlated with the tail flick behavior than with the temperature of the stimulus. These off-cells were located at sites of lowest threshold for tail flick inhibition and tended to be ventral to on-cells. We propose that off-cells must pause if the tail flick is to occur, and that this pausing allows the transmission of nociceptive input through spinal reflex loops.     

大鼠丘脑束旁核痛反应神经元放电与甩尾痛反应的联合观察

本实验以辐射热照射大鼠尾部做为伤害性刺激，可同时引起丘脑束旁核中痛兴奋神经元（painexcitatoryneurons，PEN）放电增加，痛抑制神经元（paininhibitoryneurons，PIN）M电减少和甩尾反射．放电变化发生在先，甩尾反射发生在后，束旁核中PEN和PIN放电变化与甩尾反射呈显著正相关．电针“足三里”可使PEN放电频率减少，PIN的抑制时程缩短，以及甩用反射潜伏期延长．在中枢神经元放电和整体反射水平上同时呈现出镇痛效应。     

Effects of neonatal capsaicin treatment on descending modulation of spinal nociception from the rostral, medial medulla in adult rat

Stimulation-produced modulation from the rostral, medial medulla (RMM) on the spinal nociceptive tail-flick (TF) reflex and on lumbar spinal dorsal horn neuron reponses to noxious cutaneous stimulti was studied in adult rats treated as neonates with capsaicin or vehicle. In vehicle-treated rats (n = 7), both descending facilitatory and inhibitory influences on the TF reflex were produced from the RMM. At 11/23 sites in the RMM, electrical stimulation produced biphasic modulatory effects. Electrical stimulation facilitated the spinal nociceptive TF reflex at low intensities (5–25 μA) and inhibited the TF reflex at greater intensities (50–200 μA). The mean threshold intensity of stimulation to inhibit the TF reflex (cut-off time= 7.0s) was 66 μA (n = 11). At 11 of 23 sites, electrical stimulation only inhibited the TF reflex; the mean threshold intensity of stimulation to inhibit the TF reflex was 50 μA (n = 11). At one stimulation site, electrical stimulation only facilitated the TF reflex at the intensities tested (5–100 μA). In capsaicin-treated rats (n = 6), the proportion of sites from which electrical stimulation only inhibited the TF reflex was significantly less (3/27sites= 11%) than in vehicle-treated rats (11/23= 48%). The threshold intensity of stimulation to inhibit the TF reflex from these three sites was 50 μA. The number of sites RMM fronm which electrical stimulation only facilitated the TF reflex was significantly greater in capaicin-treated rats (15/27= 56%) than in vehicle-treated rats (1/23= 4%). Neither the number of sites in RMM from which electrical stimulation produced biphasic modulatory effects on the TF reflex (48% and 33%, respectively) nor the intensities of stimulation or magnitudes of facilitation or inhibition of the TF reflex significantly differed between vehicle- and capsaicin-treated rats. In electrophysiological experiments, all units studied responded to non-noxious and noxious intensities of mechanical stimulation applied to the glabrous skin of the plantar surface of the ipsilateral hind foot and also to noxious heating of the skin (50°C). The number of sites where electrical stimulation produced only facilitatory effects on responses of spinal dorsal horn neurons to noxious stimulation (thermal or mechanical) of the skin was significantly increased from 13% of the total sites in vehicle-treated rats to 40% in capsaicin-treated rats. The number of sites where stimulation only produced inhibitory effects on responses of spinal dorsal horn neurons to noxious stimulation was decreased from 47% of the total sites in vehicle-treated rats to 35% in capsaicin-treated rats. The intensity of stimulation for producing inhibitory effects and the magnitude of inhibitory effects produced were not significantly different between vehicle- and capsaicin-treated rats. Immunocytochemical evaluation of the lumbar spinal dorsal horn verified that there were substantial reductions in substance-P and calcitonin gene-related peptide-like immunoreactivity, confirming the effectiveness of neonatal capsaicin treatment. The present study, in support of anatomical studies documenting central effects of capsaicin, suggests that neonatal capsaicin treatment also has significant effects on bulbospinal systems important to the modulation of spinal nociceptive transmission. Specifically, capsaicin treatment of neonates leads to a reduction in inhibitory and an increase in facilitatory influences on spinal nociception descending from the caudal brainstem.     

Centrifugal modulation of the rat tail flick reflex evoked by graded noxious heating of the tail

Centrifugal modulation from the midbrain, pons and medulla of the spinal nociceptive tail flick (TF) reflex evoked by graded noxious heating of the tail was studied in lightly pentobarbital-anaesthetized rats. In initial experiments, the relationship between the intensity of the noxious thermal stimulus and the TF latency was characterized. The thermal stimulus was provided by a lamp focused on the ventral surface of a rat's tail. Five different rates of heating of the tail were varied systematically by altering the voltage supplied to the lamp and were characterized using a thermocouple to measure the temperature of tissue exposed to the radiant heat. A linear stimulus-response function relating the inverse of the latency of the TF to the rate of heating of the tail was established. However, the mean cutaneous tissue temperature of the exposed tail at the time of the TF was found to be invariant and independent of the rate of heating. Focal electrical stimulation in the midbrain, pons and medulla modulated the TF reflex in two different ways, analogous to modulations of stimulus-response functions of single-cell recordings of spinal dorsal horn neurons. A Type I modulation, analogous to the parallel shift in response threshold seen in spinal dorsal horn neurons, was an absolute increase in the thermal threshold of the TF reflex. A Type II modulation, analogous to a change in slope or gain seen in spinal dorsal horn neurons, was a linear increase in the thermal threshold of the TF reflex as a function of the rate of heating. Type I modulations were produced by electrical stimulation in the ventromedial medulla (n. raphe magnus and n. reticularis gigantocellularis) and lateral periaqueductal gray of the midbrain. Type II modulations were produced by electrical stimulation in the dorsolateral pons, locus coeruleus-subcoeruleus and in the medial periaqueductal gray. This experimental approach has shown itself to be useful in the characterization of descending inhibition of nociception. Much simpler and less invasive than analogous spinal dorsal horn single cell electrophysiologic studies, it can be used to study the mechanisms of centrifugal modulation of nociceptive flexion reflexes and further establishes the utility of the lightly anaesthetized rat preparation for studies of nociception-antinociception.     

Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors

Modulation of the spinal nociceptive tail flick (TF) reflex by electrical stimulation of subdiaphragmatic or cervical vagal afferent fibers was characterized in rats lightly anesthetized with pentobarbital. Cervical vagal afferent stimulation (VAS) inhibited the TF reflex in a pulse width-, frequency-, and intensity-dependent fashion. The optimum parameters for inhibition of the TF reflex were determined to be 2.0 ms pulse width, 20 Hz frequency with a threshold (T) current of 60 microA. Cervical VAS at 0.2-0.6 T facilitated the TF reflex. Cervical VAS at T typically produced a depressor arterial blood pressure response, but inhibition of the TF reflex by VAS was not due to changes in blood pressure. Subdiaphragmatic VAS also inhibited the TF reflex and generally produced a pressor effect, but did not facilitate the TF reflex at intensities of stimulation less than T as did cervical VAS. The parameters of cervical VAS required for inhibition of TF reflex suggest that excitation of high-threshold, unmyelinated fibers are important in VAS-induced descending inhibition. The intrathecal administration of pharmacologic receptor antagonists into the subarachnoid space of the lumbar enlargement indicated that the opioid receptor antagonist naloxone produced a dose-dependent antagonism of cervical VAS-produced inhibition of TF reflex, but single doses of either phentolamine or methysergide (30 micrograms each) failed to affect the inhibition by VAS. Combined intrathecal injection of both phentolamine and methysergide (30 micrograms each), however, significantly attenuated inhibition of the TF reflex by cervical VAS. These results suggest that cervical VAS engages a spinal opioid system and co-activates descending serotonergic and noradrenergic systems to modulate spinal nociceptive processing.     

Analgesia from electrical stimulation of the hypothalamic arcuate nucleus in pentobarbital-anesthetized rats

Inhibition of noxious heat-induced tail flick by electrical stimulation of the arcuate nucleus of the hypothalamus (ARH) was examined and characterized in pentobarbital-anesthetized rats. Systematic mapping studies revealed that inhibition of the tail flick reflex could be induced by stimulating widespread areas in the ventromedial parts of the hypothalamus, which include the paraventricular nucleus, ventromedial nucleus, dorsomedial nucleus, anterior hypothalamic area as well as the ARH areas. The ARH stimulation-produced tail flick suppression could be completely blocked by systemic naloxone (2 mg/kg) which shows the involvement of an opiate mechanism in this effect. Although the tail flick reflex in the lightly anesthetized state is of significantly shorter latency than in the unanesthetized state, thresholds of the ARH stimulation for suppressing spinal nociceptive reflexes in the lightly anesthetized state were not significantly different from the thresholds at the same ARH sites in the awake state.     

Failure to produce a non-opioid foot shock-induced antinociception in rats

Brief continuous foot shock reportedly produces a naloxone-insensitive and thus non-opioid form of antinociception. In the present study, current intensity and duration of foot shock were varied: lower current intensities (0.5 or 1 mA) failed to produce a significant increase in tail flick (TF) latency, while current intensities of 3 mA and 6 mA applied for 2 or 3 min produced significant and long-lasting inhibition of the nociceptive TF reflex. Naloxone pretreatment attenuated significantly the antinociception developed at 3 mA but failed to affect that produced at 6 mA. It was noted, however, that higher current intensities damage the tail and the antinociceptive efficacy of footshock was reevaluated under conditions when the tail of the animal was not allowed to contact the electrified grid during foot shock. A significant short-lasting antinociception was produced only at the 6 mA current intensity. This antinociception could be attenuated by naloxone pretreatment, developed tolerance over time (8 days) and exhibited cross-tolerance with morphine, thus characterizing it as opioid in nature. These results raise the question to what extent damage to the tail contributes to the non-opioid foot shock-induced antinociception assessed using the nociceptive TF reflex.     

Different endogenous analgesia systems are activated by noxious stimulation of different body regions

Noxious pinch of the neck and the base of the tail can produce equipotent analgesia as measured by the tail flick method. However, noxious stimulation of the neck can suppress pain responsiveness both at the site of stimulation and at sites remote from the stimulated area while noxious stimulation of the tail produces analgesia only at sites remote from the stimulated area. Thus, neck pinched animals are immobile and completely unresponsive to the noxious pinch whereas pinch to the base of the tail, which results in tail flick suppression, causes vocalization and well organized biting behavior directed at the pinched area. The analgesia elicited by noxious stimulation applied to both body regions is eliminated by spinalization, the administration of intermediate doses of barbiturates (30 and 45 mg/kg) and transection at the midcollicular, but not more rostral, brain level. Concurrent with the elimination of the analgesic effect of noxious pinch on tail flick is the emergence of responses to noxious neck pinch with vocalization and intense motor reactions now elicited by noxious stimulation of the nape of the neck. These results indicate that different analgesic systems are activated by noxious tail and neck pinch both requiring the integrity of mesencephalic structures for their normal function. Furthermore, these systems can be distinguished by their ability to produce recurrent, inhibitory, supraspinal effects on nociceptive information originating at different body regions.     

The effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.¹⁹) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n =34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160–200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115–160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the Aβ evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160–200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.     

Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat

The influence of midthoracic spinalization on thermally and mechanically induced spinal withdrawal reflex responses was studied in the rat. There were three experimental groups of rats: healthy controls, rats with a spinal nerve ligation-induced unilateral neuropathy, and rats with a carrageenan-induced inflammation of one hindpaw. Tail flick response was induced by radiant heat. Hindlimb withdrawal was induced by radiant heat, ice water, and innocuous or noxious mechanical stimulation of the paw. Prior to spinalization, spinal nerve ligated and carrageenan-treated animals had a marked unilateral allodynia and hyperalgesia. Spinalization tended to induce a facilitation of noxious heat-evoked reflexes. This spinalization-induced facilitation was stronger on tail than hindlimb withdrawal. Spinalization-induced skin temperature change did not explain the facilitation of noxious heat-evoked reflexes. In contrast, spinal withdrawal responses induced by noxious cold or mechanical stimulation were significantly suppressed following spinalization. The spinalization-induced facilitatory effects as well as inhibitory ones on spinal reflexes were enhanced in inflamed/neuropathic animals. The results indicate that the tonic descending control of spinal nocifensive responses varies depending on the submodality of the test stimulus, the segmental level of the reflex (tail vs. hindlimb), and on the pathophysiological condition.     

Effects of stimulation of superior colliculus on nociceptive unit discharges in parafascicular neurons and nocifensive reflex of hind limb in rat

Effects of stimulation of the superior colliculus (SC) on the spontaneous and nociceptive discharges of parafascicular (PF) neurons were investigated in 43 urethane-anesthetized rats. Two groups of PF cells were sampled according to their responses to noxious stimuli: 59 of them were 'nociceptive-on' and 12 'nociceptive-off'. Following stimulation of the intermediate and deep layers of SC, the firing rate of nociceptive discharge of 'nociceptive-on' cells was inhibited significantly (-76 +/- 5%, P less than 0.01) in 75% cases tested, while the nociceptive response of 'nociceptive-off' cells was disinhibited markedly (79 +/- 9%, P less than 0.01) in 67% cases by the same stimulation. In 30 animals of this series the latency of hind limb withdrawal reflex elicited by noxious skin heating was compared before and after SC stimulation. In 24 cases in which the stimulating electrodes were positioned exactly in intermediate-deep layers of SC, SC stimulation lengthened the latency by 62 +/- 8% (P less than 0.01), while in 6 cases in which the electrodes drifted from these areas, the latency was not changed following the same stimulation.     

A Quantitative Model of the Hoffmann Reflex

Abstract

Electrical stimulation of the human posterior tibial nerve elicits two separate electromyographic responses. The shorter latency response results from electrical activation of motor axons and is termed the direct motor (M) response, while the longer latency response results from activation of stretch receptor afferents of the monosynaptic reflex arc and is termed the Hoffmann (H) reflex. At high stimulus intensities, the H reflex is either greatly reduced in size or completely extinguished, presumably by antidromic impulses elicited by stimulation of the motor nerve. In most subjects, a simple quantitative model appears to account for this extinction. In this model: (1) the M response is used to estimate the number of antidromic impulses; (2) the H reflex is used to estimate the number of orthodromic impulses which escape collision; (3) the maximum size of the M response is used to indicate the size of the motoneuron pool; and (4) it is assumed ,that antidromic impulses collide in a random fashion with orthodromic impulses in the motor nerve.     

Spinal cholinergic and monoamine receptors mediate the antinociceptive effect of morphine microinjected in the periaqueductal gray on the rat tail, but not the feet

The antinociceptive effects of morphine (5 μg) microinjected into the ventrolateral periaqueductal gray were determined using both the tail flick and the foot withdrawal responses to noxious radiant heating in lightly anesthetized rats. Intrathecal injection of appropriate antagonists was used to determine whether the antinociceptive effects of morphine were mediated byα₂-noradrenergic, serotonergic, opioid, or cholinergic muscarinic receptors. The increase in the foot withdrawal response latency produced by microinjection of morphine in the ventrolateral periaqueductal gray was reversed by intrathecal injection of the cholinergic muscarinic receptor antagonist atropine, but was not affected by the a2-adrenoceptor antagonist yohimbine, the serotonergic receptor antagonist methysergide, or the opioid receptor antagonist naloxone. In contrast, the increase in the tail flick response latency produced by morphine was reduced by either yohimbine, methysergide or atropine. These results indicate that microinjection of morphine in the ventrolateral periaqueductal gray inhibits nociceptive responses to noxious heating of the tail by activating descending neuronal systems that are different from those that inhibit the nociceptive responses to noxious heating of the feet. More specifically, serotonergic, muscarinic cholinergic andα₂-noradrenergic receptors appear to mediate the antinociception produced by morphine using the tail flick test. In contrast, muscarinic cholinergic, but not monoamine receptors appear to mediate the antinociceptive effects of morphine using the foot withdrawal response.     

Inhibitory effect of stimulation of the anterior pretectal nucleus on the jaw-opening reflex

The anterior pretectal nucleus (APT) has been recently implicated in sensorimotor integration and has been shown to have suppressive influences on tail flick behaviour and on nociceptive responses of spinal dorsal horn neurones in rats. The present study tested the effect of stimulation of the APT on the rat's digastric jaw-opening reflex elicited by orofacial stimuli. Either ipsilateral or contralateral electrical stimulation at histologically confirmed sites within and immediately subjacent to the APT produced a suppression of the reflex that had an onset of 20–30 ms, peaked around 50 ms and lasted for 200–300 ms; in some cases, a brief period of reflex facilitation preceded the onset of inhibition was sometimes followed by a facilitatory period. No prolonged period of suppression induced by electrical stimulation was noted in these anaesthetized rats. The injection of monosodium glutamate at comparable sites within and subjacent to APT induced reflex suppression that lasted several minutes. These findings represent the first documentation of APT-induced modulation in the trigeminal sensorimotor system, but support recent evidence suggesting the involvement of APT in sensorimotor integration and modulation.     

Spinal antinociception mediated by a cocaine-sensitive dopaminergic supraspinal mechanism

The role of dopaminergic descending supraspinal processes in mediating the antinociceptive action of cocaine was studied in the rat using a combination of extracellular neuronal recording and behavioral techniques. Neurons in the superficial laminae (I-II) of the spinal dorsal horn with receptive fields on the tail were recorded in anesthetized rats using insulated metal microelectrodes. Stimulation of the receptive field with either high intensity transcutaneous electrical pulses or with an infrared CO₂ laser beam produced a biphasic increase in dorsal horn unit discharge. Conduction velocity estimates indicated that the early discharge corresponded to activity in Aδ whereas the late response corresponded to activity in C afferent fibers. Cumulative doses of cocaine (0.1–3.1 mg/kg i.v.) inhibited the late response to either electrical or laser stimulation in a dose-related manner. The early response to laser, but not electrical, stimulation was also suppressed by cocaine. Neurons in the spinal dorsal horn with receptive fields on the ipsilateral hindpaw were activated by natural noxious (pinch) or innocuous (tap) somatic stimulation. Cocaine selectively suppressed nociceptively evoked dorsal horn unit discharge. This antinociceptive effect was dose-related (0.3–3.1 mg/kg, i.v.) and antagonized by eticlopride (0.05–0.1 mg/kg, i.v.), a selective D2 dopamine receptor blocker. The same doses of cocaine failed to inhibit the responses of dorsal horn neurons to low threshold innocuous stimulation. Complete thoracic spinal cord transection eliminated the antinociceptive effect of cocaine on dorsal horn neurons and also eliminated the cocaine-induced attenuation of the tail-flick reflex. These data demonstrte that cocaine selectively inhibits nociceptive spinal reflexes and the nociceptive responses of dorsal horn neurons primarily by means of a D2 dopaminergic receptor mechanism. This antinociceptive effect of cocaine is independent of its local anesthetic activity and requires the integrity of the thoracic spinal cord, suggesting that the drug potentiates or activates supraspinal dopaminergic projections to the dorsal horn.     

Differential inhibition produced by peripheral conditioning stimulation on noxious mechanical and thermal responses of different classes of spinal neurons in the cat

The effect of conditioning stimulation of a peripheral nerve on responses of spinal neurons (dorsal horn cells and motoneurons) was studied in 16 decerebrate-spinal cats. The activity of dorsal horn cells was recorded with a microelectrode at the lumbosacral spinal cord and the single-unit activity of motoneurons was recorded from a filament of ventral rootlet divided from either the L7 or S1 ventral root. The responses of spinal neurons were evoked by noxious and innocuous mechanical stimuli and by noxious thermal stimuli applied to the receptive fields. The peripheral conditioning stimulation was applied to the tibial nerve with repetitive electrical pulses (2 Hz) at an intensity either suprathreshold for A delta or C fibers for 5 min. Applying conditioning stimulation to a peripheral nerve produced a powerful inhibition of the responses elicited by noxious stimuli, suggesting this inhibition is an antinociceptive effect. The inhibition produced by peripheral conditioning stimulation was differentially greater on the responses to noxious than to innocuous stimuli. Based on the results obtained from conditioning stimulation with graded strengths, afferent inputs from both myelinated and unmyelinated fibers seem to contribute to the production of the antinociceptive effect. The magnitude of the antinociceptive effect is bigger for the responses to noxious thermal than to mechanical stimuli. Furthermore, the reflex activity recorded in motor axons seemed to be more sensitive than in dorsal horn cells to the antinociceptive effect.     

Spinal monoamine mediation of stimulation-produced antinociception from the lateral hypothalamus

Stimulation-produced antinociception can be evoked from a wide variety of sites in the brain, including the lateral hypothalamus (LH). The present study, in rats lightly anesthetized with pentobarbital, examined descending inhibition of the nociceptive tail flick (TF) reflex produced by focal electrical stimulation in the LH and the neurotransmitter(s), at the level of the lumbar enlargement, mediating the inhibition. Systematic tracking studies demonstrated that stimulation in the diencephalon dorsal to the hypothalamus did not reliably inhibit the TF reflex. Inhibition of the TF reflex was produced, however, throughout the hypothalamus at intensities of stimulation typically between 50 and 200 μA. The area requiring low intensities of stimulation (50–100 μA) to inhibit the TF reflex was a diffuse region of the LH, inferior to the mammillothalamic tract and internal capsule, medial to the supraoptic decussation and including the medial forebrain bundle. Microinjections of S-glutamate (100 mM, 0.5μl) in the LH did not inhibit the TF reflex, suggesting that activation of fibers of passage by stimulation was responsible for inhibition of the TF reflex produced from the LH. The intrathecal administration of pharmacologic antagonists (15–30 μg; naloxone, methysergide, phentolamine, prazosin or yohimbine) revealed that the α-adrenoceptor antagonists phentolamine and yohimbine produced the greatest increases in stimulation thresholds in the LH for inhibition of the TF reflex (83.7% and 89.8%, respectively). The intrathecal administration of methysergide produced a lesser, but statistically significant 11% increase in the stimulation threshold for inhibition of the TF reflex. These results indicate that spinal α₂-adrenoceptors primarily mediate the descending inhibition of the TF reflex produced by electrical stimulation in the LH.     

Is the cutaneous silent period an opiate‐sensitive nociceptive reflex?

In humans, high-intensity electrical stimuli delivered to the fingers induce an inhibitory effect on C7-T1 motoneurons. This inhibitory reflex, called the cutaneous silent period (CSP) is considered a defense response specific for the human upper limbs. It is not clear whether the CSP-like other defense responses such as the corneal reflex and the R III reflex-is an opiate-sensitive nociceptive reflex. Because opiates suppress some, but not all, nociceptive reflexes, we studied the effect of the narcotic-analgesic drug fentanyl on the CSP and the R III reflex. The CSP was recorded from the first dorsal interosseous (FDI) muscle in seven normal subjects during voluntary contraction, before and 10 and 20 min after fentanyl injection. To assess possible fentanyl-induced changes, we also tested the effect of finger stimulation on motor evoked potentials (MEPs) elicited in the FDI muscle by transcranial magnetic stimulation before and after fentanyl injection. Fentanyl-induced changes were also studied on the R III reflex recorded from the biceps femoris muscle. Fentanyl, as expected, suppressed the R III reflex but failed to change the inhibitory effect of finger stimulation on FDI motoneurons. Finger stimulation reduced the size of MEPs in the FDI, and fentanyl injection left this inhibitory effect unchanged. The differential fentanyl-induced modulation of the CSP and R III reflex provides evidence that the CSP circuit is devoid of mu-opiate receptors and is therefore an opiate-insensitive nociceptive reflex, which may be useful in the assessment of central-acting, non-opioid drugs.