Properties of functionally identified nociceptive and nonnociceptive facial primary afferents and presynaptic excitability changes induced in their brain stem endings by raphe and orofacial stimuli in cats

The activity of 221 single primary afferent units was recorded extracellularly in the trigeminal (V) ganglion of chloralose-anaesthetized cats to examine the receptive field properties of nonnociceptive and nociceptive cutaneous afferents and the effect of conditioning stimulation of the raphe system and orofacial afferents on the antidromic excitability of their brain stem endings in V subnucleus caudalis. In addition to slowly adapting and rapidly adapting low-threshold mechanosensitive afferents, we functionally identified three classes of cutaneous nociceptive afferents: these included A-delta high-threshold mechanoreceptive afferents (A-delta HTMs), C-fiber high-threshold mechanoreceptive afferents (C-HTMs), and C-polymodal nociceptive afferents (CPNs). Most of the CPNs could be activated by light tactile stimuli as well as by heavy pressure and pinch and noxious radiant heat applied to their mechanoreceptive field which usually involved a localized spot (approximately 1 mm in diameter) of skin. In contrast, the C-HTMs and A-delta HTMs could not be activated by radiant heat stimuli although some did show sensitization which was also a feature of the CPNs; they did respond to noxious mechanical stimulation of a localized area of skin. We noted that orofacial conditioning stimulation could produce an increase in antidromic excitability which was considered a reflection of primary afferent depolarization (PAD) in both nociceptive and nonnociceptive afferents innervating the cat's facial skin; nonnoxious mechanical stimuli and electrical stimuli were particularly effective in the low-threshold mechanosensitive afferents and noxious mechanical and high-intensity electrical stimuli were especially effective in the cutaneous nociceptive afferents. Raphe conditioning stimulation also was very effective in inducing PAD in these nociceptive afferents; however, the raphe conditioning effects were not limited to these nociceptive afferents since PAD was also frequently demonstrated in the low-threshold mechanosensitive afferents.     

Response properties of nociceptive and low-threshold mechanoreceptive neurons in the hamster superior colliculus

There are many somatosensory neurons in the hamster superior colliculus (SC); some respond to innocuous tactile stimuli, while others respond either preferentially, or solely, to noxious stimuli. Yet, there are little quantitative data describing the responses of these neurons. We sought to provide such information by relating stimulus intensity to the magnitude of the neural response using controlled innocuous and noxious mechanical and thermal stimuli. Of 122 somatosensory SC neurons studied in urethane-anesthetized hamsters, the majority (52%) had low-threshold mechanoreceptive properties (LT). LT neurons had force thresholds less than 1 gm, adapted rapidly to maintained stimuli, and did not respond with higher numbers of impulses to noxious mechanical or thermal stimuli. A smaller, though substantial, proportion of neurons (45%) responded either preferentially, or solely, to noxious stimuli. A few neurons (3%) were inhibited by either light tactile or noxious mechanical stimuli. Two populations of nociceptive neurons were found and classified either as wide dynamic range (WDR) neurons (n = 25), those that responded to gentle mechanical, noxious mechanical, and/or thermal stimuli; or nociceptive-specific (NS) neurons (n = 30), those that responded solely to high-intensity mechanical or noxious thermal stimuli. WDR neurons responded monotonically to increases in the intensity of innocuous mechanical stimuli, and displacement-response relationship for this population was a slightly negatively accelerating power function with an exponent of 0.785. However, the thermal stimulus-response relationships (to graded skin temperatures) of both WDR and NS neurons were positively accelerating power functions with exponents of 2.3 and 2.5 (r2 = 0.988), respectively. These values are consistent with both electrophysiological data from dorsal horn nociceptive neurons and from human psychophysical results using the same range of thermal stimuli. These experiments demonstrate that SC neurons are capable of signaling not only the presence and location of a noxious stimulus but its intensity as well. Presumably, these neurons play a significant role in the animal's reactions to potentially harmful stimuli. The partial laminar segregation of WDR and NS neurons may reflect different involvements of particular nociceptive subtypes in the various overt responses mediated by the SC.     

The morphology of dorsal column postsynaptic spinomedullary neurons in the cat

Dorsal column postsynaptic (DCPS) spinomedullary neurons from the cat's lumbosacral enlargement were identified by antidromic stimulation of the cervical dorsal columns and stained intracellularly with horseradish peroxidase. The cell bodies were located in laminae III-IV. Their dendritic arbors were elongated rostrocaudally but narrow mediolaterally. On the average, the arbors were ×5 longer than they were wide. Most of the neurons had nearly all of their dendrites in laminae III-IV and some of the neurons had, in addition, a considerable amount of dendritic surface area in lamina V. Only one neuron had more than a very small amount of dendritic surface area dorsal to lamina III. Seven of the neurons had unmyelinated axon collaterals that arborized extensively and issued varicosity-bearing terminal branches in laminae III-V, both within and beneath their dendritic territories. All of the neurons were excited by myelinated, low-threshold mechanoreceptors. Since the rostrocaudally elongated and mediolaterally narrow dendritic arbors of DCPS neurons are in register with the laminae III-IV terminal distributions of myelinated, low-threshold mechanoreceptors, it is probable that this excitation arises from a monosynaptic and topographically discrete innervation. About one-half of the DCPS neurons were also excited by noxious stimuli. It is probable that this excitation is accomplished by a polysynaptic distributions are largely or completely separate.     

Extra- and intracellular recordings from dorsal column postsynaptic spinomedullary neurons in the cat

Dorsal column postsynaptic (DCPS) spinomedullary neurons in the dorsal horn of spinal segments L6-S1 of adult cats anesthetized with sodium pentobarbital were identified by antidromic stimulation of cervical dorsal columns that were dissected free of, and electrically isolated from, the rest of the spinal cord. The neurons were categorized with respect to natural stimulation of their cutaneous receptive fields. An equal number of low-threshold mechanoreceptive and wide-dynamic-range neurons were found. No DCPS neurons could be classified as nociceptive-specific. All neurons received input from low-threshold mechanoreceptors with myelinated axons. There was no evidence that any neurons received monosynaptic input from unmyelinated, primary afferent fibers. The average conduction velocity of the antidromic responses was 45.7 m/s. Nearly half of the DCPS cells showed an antidromic spike followed by synaptically driven responses that were probably evoked by antidromic invasion into the intraspinal collaterals of A-beta primary afferent fibers that ascended the dorsal columns. Intracellularly recorded synaptic responses of DCPS neurons to dorsal column and receptive field stimulation usually consisted of an EPSP with overriding spike potentials followed by a prolonged IPSP whose amplitude decreased markedly as the stimulus frequency was increased in the range of 5 to 30 Hz. The results indicate that DCPS neurons constitute a projection system capable of signaling innocuous and tissue-damaging mechanical stimuli. The DCPS projection may play a role in the modulation of touch and pain perception.     

Responses of trigeminal subnucleus interpolaris neurons to afferent inputs from deep oral structures.

Responses of trigeminal subnucleus interpolaris neurons to natural and electrical stimulation of the temporomandibular joint (TMJ) and the masseter muscle (Mm) were studied in the anesthetized rat. Interpolaris neurons could be placed in one of three classes determined by their responses to noxious and innocuous stimuli: Class I, excited by only innocuous stimuli; Class II, excited by only noxious stimuli; Class III, excited by both. In each class, the conduction velocities of the primary afferents were roughly equivalent to those of small-diameter fibers. Approximately 70% of the interpolaris neurons tested received nociceptive inputs from the TMJ and/or the Mm. Most of these neurons had extensive convergence of afferent inputs, including the TMJ, the Mm, and/or the facial skin. The results suggest involvement of interpolaris neurons in the characteristics of deep pain, such as its spread and referral.     

Morphological features of lamina V neurons receiving nociceptive input in cat sacrocaudal spinal cord

Thirty-six neurons from laminae III-VII in cat sacrocaudal spinal cord were labeled by intracellular injection of horseradish peroxidase, following physiological characterization. Of these 36 neurons, 24 had cell bodies within lamina V. Twelve lamina V neurons were multireceptive; i.e., they responded differentially to innocuous and noxious mechanical stimuli. Most multireceptive neurons had the following morphological features: (1) large cell bodies; (2) extensive dendritic spreads in all directions; and (3) axons which ascended in the contralateral ventral white matter. Three labeled lamina V neurons were activated only by noxious stimuli. Compared to the multireceptive neurons, these nociceptive-specific (NS) units had smaller cell bodies but a similar dendritic spread. Seven lamina V neurons were excited by innocuous mechanical stimuli with no evidence of nociceptive input. These seven neurons had less extensive dendritic trees than the multireceptive and the NS neurons. Six neurons labeled in lamina VII (three multireceptive and three NS) contrasted to most lamina V cells by having smaller cell bodies and short, sparsely branched dendrites. Among the lamina VII neurons, there was no obvious morphological feature that distinguished the multireceptive group from the NS group. Fifteen fully stained neurons from laminae III-VII had late discharges which were correlated with C fiber input. The dendrites of three of these neurons extended into laminae II and I; the dendrites of two neurons reached into the inner portion of lamina II; and the dorsal dendrites of the remaining ten neurons extended no further than the nucleus proprius (laminae III and IV). Thus, deeper dorsal horn neurons evincing reliable, excitatory influences from C fibers do not necessarily have superficially situated dendrites. Tests for correlations between size of cutaneous, excitatory receptive field (RF) and dendritic spread revealed a significant positive correlation between the mediolateral extent of dendritic spread and the size of the low-threshold component of the RF for lamina V neurons.     

Single unit activity at ventromedial medulla level in the awake, freely moving rat: effects of noxious heat and light tactile stimuli onto convergent neurons

In this study, we recorded single unit activity at the ventromedial medulla (VMM) level in the awake, freely moving rat. In agreement with previous work under the same conditions, we found a vast majority of neurons which possess heterosensory and heterosegmental inputs ('convergent'). These units are activated either by auditory or mechanical innocuous and noxious stimuli applied all over the body surface. The activation threshold of these neurons is very low since light stimulation such as air puff produce intense bursts. In addition to this highly represented neuronal class, we also find another consistent VMM group of neurons which fire in relation to precise or generalized body movements. The main result of the present work is that, in addition to auditory and mechanical inputs, a relatively high proportion of VMM convergent neurons are activated by noxious heat pulses between 43 and 51 degrees C. In this range, it was possible to obtain stimulus-response functions with 2 degrees C steps only when a skin twitch reflex produced by the heat was present, also encoding the temperature intensity. In comparison to the VMM activations produced by an intense noxious heat pulse such as 51 degrees C, either auditory or controlled light touch stimuli induced a more robust response in terms of maximum frequency of discharge. Differential properties of VMM neurons in relation to innocuous and noxious information were also found using repetitive stimulation: although a strong and fast habituation of the 51 degrees C responses was observed, this phenomenon was not present for light touch induced activations. We propose that these differential properties might reflect separate pathways reaching the VMM, the one carrying innocuous information possibly relayed through the dorsal column nuclei. Although obtaining stimulus-response functions might implicate the VMM convergent neurons in the sensory-discriminative aspect of pain, their massive heterosensory and heterosegmental inputs favor a role in more general processes such as alertness or stress. Also, due to massive convergent properties, the involvement of this neuronal class in specific bulbospinal descending control systems of nociceptive information is questionable, Finally, our results obtained in the awake, freely moving rat strongly differ from the anesthetized preparation in that we found neither nociceptive specific units nor neurons inhibited by noxious peripheral stimulations largely described in this approach.     

Properties of feline thalamic neurons activated by stimulation of the middle meningeal artery and sagittal sinus

Previous studies have identified a population of neurons in the cat trigeminal brainstem complex that respond to stimulation of the middle meningeal artery (MMA) and/or superior sagittal sinus (SS). In the present study, neuronal responses to stimulation of the MMA and SS were sought in the thalamus of the cat. Sixty-one neurons excited by electrical stimulation of the MMA and/or SS were located in the ventroposteromedial (VPM) nucleus, and surrounding regions in lateral thalamus. Of these 61 neurons, 23% were excited only by MMA stimulation, 39% only by SS stimulation and 38% by both MMA and SS stimulation. The latencies to activation from MMA and/or SS stimulation suggest the involvement of small, myelinated primary afferent fibers. Most neurons (48/61) responded to electrical stimulation of the MMA or SS with a burst of 2-5 spikes. Mechanical stimulation of the MMA and SS was also an effective stimulus and in some cases evoked a burst response. Of the neurons tested for the existence of orofacial inputs, all were found to have an excitatory receptive field (RF) on the face and usually (22/26 neurons) involved the ophthalmic distribution. Twelve of these neurons were excited by a tap stimulus applied to the face, 6 by pinching (nociceptive specific), 6 by low-threshold mechanical stimuli (LTM), one by both pinch and low-threshold stimuli and one by mechanical stimulation of the cornea. The firing properties, RF and modalities of these thalamic neurons suggest that they may play a role in the appreciation of pain of cerebrovascular origin.     

Physilogy and morphology of substantia gelatinosa neurons intracellularly stained with horserdish peroxidase

Neurons in Rexed's layer II were physiologically characterized with natural and electrical stimuli applied to their cutaneous receptive field. The neurons were then intracellularly stained with horseradish peroxidase. Three general patterns of physiological responses were found Nociceptive specific neurons did not respond to gentle mechanical stimulation. Most responded exclusively to tissue-damaging stimuli. Some also responded to moderately heavy pressure, but these responded to noxious stimuli with an increased discharge frequency. Wide dynamic range neurons responded to both gentle mechanical stimulation and to tissue-damaging stimulation. Low-threshold mechanoreceptive neurons responded only to gentle mechanical stimulation. Some of the low-threshold mechanoreceptive neurons were innervated by primary afferents with unmyelinated axons. Excepting those low-threshold mechanoreceptive neurons with input form unmyelinated afferents, the patterns of primary afferent innervation of layer II neurons were similar to the patterns innervation that gave been found for neurons in layers I and IV-V. All nut 2 of the 22 neurons that we found were recognized as being of two general morphological types. Stalked cells had their perikarya situated along the superficial border of layer II. Most of their dendrites traveled ventrally while spreading out rostrocaudally. This gave their dendritic arbors a fan-like shape. Stalked cell axons arborized largely in layer I. Islet cell perikarya were found throughout layer II. Most of their dendrites traveled rostrocaudally. Their dendritic arbors were shaped like cylinders with their long axes parallel to the long axis of the spinal cord. Islet cell axons arborized in the immediate vicinity of their dendtritic territories, within layer II. Stalked cells and those islet cells whose dendritic arbors were largely contained within the superficial one-third of layer II (layer IIa) were either nociceptive specific or wide dynamic range neurons. The islet cells whose dendritic arbors were largely within the deeper two-thirds of layer II (layer IIb) were all low-threshold mechanoreceptive neurons. These observations suggest that layers IIa and IIb have different functional roles and that stalked cells and islet cells are separate and distinct components of the neural circuitry of the superficial dorsal horn.     

Human microneurography and intraneural microstimulation in the study of neuropathic pain

Psychophysical experiments in combination with microneurography and intraneural microstimulation in awake human subjects have yielded some useful information on somatosensory functions under normal and pathologic conditions. Normally, pain is signaled by nociceptive afferents, and tactile sensations are evoked from activation of low-threshold mechanoreceptors. Following tissue injury, nociceptors are sensitized, and their enhanced responsiveness correlates with hyperalgesia to heat and in some cases to mechanical stimuli. In addition, ongoing activity in sensitized nociceptive afferents may lead to central sensitization in such a way that normally nonpainful gentle stroking the skin evokes pain from activation of low-threshold mechanoreceptors. This particular change in signal processing in the central nervous system is restored when the ongoing nociceptive input is interrupted, whereas other forms of central sensitization can outlast the duration of the nociceptive input. © 1993 John Wiley & Sons, Inc.     

An alpha 2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones

Extracellular recordings were made of 59 neurones with long, ascending projections (spinocervical tract (SCT) and dorsal column postsynaptic (DCPS) neurones) in the lumbar dorsal horn of anaesthetized and paralyzed cats. All showed prominent excitatory responses to innocuous stimuli, applied to their cutaneous receptive fields on the ipsilateral hindlimb. The majority of the population investigated (83%) was multireceptive, being activated by noxious as well as innocuous cutaneous stimuli. Drug effects were examined on a regular cycle of responses to these cutaneous stimuli and also to DL-homocysteic acid (DLH). In 49 multireceptive SCT and DCPS neurones, ionophoretically-applied L-noradrenaline (NA) produced a potent selective inhibition of the nociceptive responses (to heat or pinch) in 40 out of 44 SCT and 3 out of 5 DCPS neurones, with no statistically significant change in the responses to innocuous brush or DLH, or in spontaneous activity. NA had no effect on the majority of cells (8 out of 11) that responded only to innocuous stimuli. In 19 SCT neurones that showed NA-selectivity, the alpha 2-selective agonists clonidine (in 12 out of 15) and metaraminol (in 2 out of 3) mimicked this selective effect, whereas, the alpha 1 agonist, phenylephrine and the beta agonist, isoprenaline did not. Furthermore, the alpha 2 antagonists, yohimbine and idazoxan (RX781094), either reversed or reduced the potency of the NA-elicited inhibition of nociceptive responses in all 7 SCT neurones tested. These results are discussed in relation to other evidence for spinal antinociceptive effects of noradrenergic systems acting at a spinal level and the possible involvement of an alpha 2 receptor in such effects.     

Thermoreceptors and thermosensitive afferents

Cutaneous thermosensation plays an important role in thermal regulation and detection of potentially harmful thermal stimuli. Multiple classes of primary afferents are responsive to thermal stimuli. Afferent nerve fibers mediating the sensation of non-painful warmth or cold seem adapted to convey thermal information over a particular temperature range. In contrast, nociceptive afferents are often activated by both, painful cold and heat stimuli. The transduction mechanisms engaged by thermal stimuli have only recently been discovered. Transient receptor potential (TRP) ion channels that can be activated by temperatures over specific ranges potentially provide the molecular basis for thermosensation. However, non-TRP mechanisms are also likely to contribute to the transduction of thermal stimuli. This review summarizes findings regarding the transduction proteins and the primary afferents activated by innocuous and noxious cold and heat.     

Responses of neurons in the nucleus basalis of Meynert to various afferent stimuli in rats

The effects of innocuous and noxious mechanical stimulation of skin, and of baroreceptor and chemoreceptor stimulation, on the activity of single neurons in the nucleus basalis of Meynert (NBM), whose axons project to the cortex, were examined in urethane-anesthetized adult rats. Most of the neurons were not significantly influenced by innocuous mechanical cutaneous stimulation or baroreceptor stimulation, while they were excited by noxious mechanical cutaneous stimulation and chemoreceptor stimulation. The NBM neurons were excited more intensely and frequently by nociceptive mechanical stimulation to a fore- or hindpaw than by that to the back or face. The function of these NBM neurons is discussed.     

Postsynaptic dorsal column pathway of the rat. II. Evidence against an important role in nociception

The response characteristics of neurons at the origin of the postsynaptic dorsal column (PSDC) pathway were determined in unanesthetized, decerebrated, spinalized rats. Sixty-four percent of PSDC neurons responded only to innocuous mechanical stimuli. Thirty-six percent responded to innocuous stimuli but were more powerfully activated by noxious pinch. Ninety-three percent of the tested PSDC neurons were not activated by any of several intensities of sustained, repeated noxious heating of their receptive fields. The failure of pinch-responsive PSDC cells to respond to thermal stimulation, even in sensitized skin, suggests that they do not receive a functionally significant input from C polymodal nociceptors, heat nociceptors, or mechanical-heat nociceptors. We conclude, therefore, that the postsynaptic dorsal column pathway is not importantly involved in nociception in the rat.     

Effects of capsaicin applied to a peripheral nerve on the responses of primate spinothalamic tract cells

Capsaicin is a neurotoxin that appears to affect unmyelinated nociceptive sensory fibers selectively. We examined the effects of capsaicin applied topically to the sural nerve on peripheral nerve volleys and on the responses of neurons belonging to the spinothalamic tract (STT) in the monkey. The responses examined included those following electrical stimulation of the sural nerve and also those produced by more natural forms of noxious and innocuous stimuli applied to the skin. Capsaicin (1% solution) applied onto the sural nerve for 15 min resulted in a reduction of the sizes of A delta- and C-fiber afferent volleys. These changes paralleled the reduction of A- and C-fiber responses of the STT cells elicited by electrical stimulation of the sural nerve. During capsaicin application onto the sural nerve, the background activity of STT cells increased for 5-10 min. After capsaicin treatment, the responses of STT cells to innocuous mechanical stimuli applied to the cutaneous receptive field were increased, whereas the responses to noxious mechanical stimuli were decreased. However, topical capsaicin application almost eliminated the responses of STT cells to noxious heat stimuli. The results of the present study suggest that topical capsaicin application onto a peripheral nerve produces a transient nociceptive response followed by a decrease in sensitivity to noxious stimuli, particularly to noxious heat. These changes are due to conduction block of the nerve fibers at the site of capsaicin application.     

A fMRI study of brain activations during non-noxious and noxious electrical stimulation of the sciatic nerve of rats

An acute pain animal model for fMRI study would provide useful spatial and temporal information for studying the supraspinal nociceptive neuronal responses. The aim of the present study was to investigate whether the nociceptive responses in different brain areas can be differentiated by using functional magnetic resonance imaging (fMRI) in anesthetized rats. Functional changes in brain regions activated by noxious or non-noxious stimuli of the sciatic nerve were investigated using fMRI in a 4.7 T MR system in alpha-chloralose anaesthetized rats. To determine the electrical intensity for noxious and non-noxious stimuli, compound action potential recording was employed to reveal the type of fibers activated by graded electrical stimulation of sciatic nerve. It showed that innocuous A-beta fibers were excited by two times the muscle twitch threshold and nociceptive A-delta and C fibers were recruited and excited by 10 and 20 times threshold, respectively. A series of four-slice gradient echo images were acquired during innocuous (two times threshold) and noxious (10 and 20 times threshold) stimuli in a 4.7 T MR system. Contralateral somatosensory cortex was the most prominent brain area activated by innocuous stimuli. Both signal intensity and activated areas were significantly increased in the somatosensory cortex, cingulate cortex, medial thalamus and hypothalamus during noxious stimuli. These four brain areas activated by noxious stimuli were significantly suppressed by prior intravenous injection of morphine (5 mg/kg). The present findings demonstrated that the difference of the innocuous and nociceptive responses in the brain could be detected and localized by an in vivo spatial map using fMRI. Results suggest that fMRI may be an invaluable tool for studying pain in anesthetized animals.     

An α2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones

Extracellular recordings were made of 59 neurones with long, ascenfing projections (spinocervical tract (SCT) and dorsal column postsynaptic (DCPS) neurones) in the lumbar dorsal horn of anaesthetized and paralyzed cats. All showed prominent excitatory responses to innocuous stimuli, applied to their cutaneous receptive fields on the ipsilateral hindlimb. The majority of the population investigated (83%) was multireceptive, being activated by noxious as well as innocuous cutaneous stimuli. Drug effects were examined on a regular cycle of responses to these cutaneous stimuli and also todl-homocysteic acid (DLH).In 49 multireceptive SCT and DCPS neurones, ionophoretically-appliedl-noradrenaline (NA) produced a potent selective inhibition of the nociceptive responses (to heat or pinch) in 40 out of 44 SCT and 3 out of 5 DCPS neurones, with no statistically significant change in the responses to innocuous brush or DLH, or in spontaneous activity. NA had no effect on the majority of cells (8 out of 11) that responded only to innocuous stimuli.In 19 SCT neurones that showed NA-selectivity, the α₂-selective agonists clonidine (in 12 out of 15) and metaraminol (in 2 out of3) mimicked this selective effect, whereas, the α₁ agonist, phenylephrine and the β agonist, isoprenaline did not. Furthermore, the α antagonists, yohimbine and idazoxan (RX781094), either reversed or reduced the potency of the NA-elicited inhibition of nociceptive responses in all SCT neurones tested. These results are discussed in relation to other evidence for spinal antinociceptive effects of noradrenergic systems acting at a spinal level and the possible involvement of an α₂ receptor in such effects.     

Nonsegmental inhibition of rat dorsal horn neurons by innocuous stimulation

In rats anesthetized with thiamylal sodium, responses of spinal cord dorsal horn neurons to noxious skin heating of the tail were recorded by extracellular microelectrodes. Inhibition of these responses by innocuous mechanical stimulation (light brushing) of the ipsilateral forelimb was assessed. Short-lasting application (3 min, or less) of light brushing did not inhibit neuronal responses to noxious heating. Long-lasting application (5 min, or more) inhibited responses of these neurons to noxious stimulation. The results indicate that, in the anesthetized rat, remotely applied innocuous cutaneous stimuli can inhibit nociceptive responses of dorsal horn neurons, if applied for a sufficiently long time.     

Responses of rat dorsal horn neurons to natural stimulation and to iontophoretically applied norepinephrine

Extracellular recordings were obtained of 177 neurons throughout the lumbar spinal dorsal horn of urethane- or halothane-anesthetized rats. These neurons all responded to iontophoretically applied L-glutamate and their responses to natural stimulation of the ipsilateral hindlimb were characterized. Iontophoretically applied norepinephrine was tested on 94 of these neurons. Fifty-one neurons were inhibited and 22 were excited. Norepinephrine produced a biphasic inhibitory/excitatory effect on nine neurons. Norepinephrine was exclusively inhibitory on superficial dorsal horn neurons that responded only to innocuous brush and touch and on neurons in the nucleus proprius that responded to brush, touch, and noxious skin pinch. Norepinephrine excited some superficial brush/touch/pinch neurons and produced short inhibitions that were followed by prolonged excitations of some nucleus proprius neurons that responded only to noxious skin pinch. Neurons in the base of the dorsal horn that responded to low-threshold proprioceptive stimulation were excited by norepinephrine. Both the inhibitory and excitatory effects of norepinephrine were stereoselective, but they were not blocked by receptor subtype-selective antagonists. Desensitization to norepinephrine occurred for 30% of the neurons. This study demonstrates that the inhibitory effects of norepinephrine on rat dorsal horn neurons are not restricted to neurons that are responsive to noxious stimuli and that some of these neurons are primarily excited by norepinephrine. The excitatory effects of norepinephrine on low-threshold proprioceptive neurons may contribute to norepinephrine's known enhancement of spinal flexor reflex activity.