The role of the dorsal column pathway in visceral nociception

Neurosurgeons have successfully used punctate midline myelotomy to relieve visceral cancer pain in human patients. Animal experiments demonstrate a visceral nociceptive pathway in the posterior column that is more effective than the spinothalamic tract in activating thalamic neurons, eliciting behavioral responses and triggering increases in regional cerebral blood flow. This visceral nociceptive pathway involves postsynaptic dorsal column neurons in the central, visceral processing region of the spinal cord. Axons from the sacral cord ascend near the midline and from the thoracic cord at the junction of the gracile and cuneate fasciculi.     

Responses of spinal cord dorsal horn neurones to non-noxious and noxious cutaneous temperature changes in the spinal rat.

(1) Lumbar dorsal horn units characterized by their mechanical cutaneous sensitivities were tested for their responses to temperature changes of the skin in the decerebrate spinal rats. (a) Class 1 units (i.e. driven by non-noxious mechanical stimuli) were rarely thermally sensitive. (b) Nearly all class 2 units (i.e. driven by both non-noxious and noxious mechanical stimuli) and 4 of the 5 class 3 units (i.e. driven by noxious mechanical stimuli) were sensitive to temperature changes. (2) According to their thermal response threshold and their response range, these units were divided into 3 groups. (a) Warming units whose response threshold and maximum response were below 42.5 degrees C. Such units were rarely encountered. (b) Warming/noxious heat units whose response threshold was below 42.5 degrees C but with a maximum response above this temperature. They represented approximatively one-third of the radiant heat-sensitive units. (c) Noxious heat units whose response threshold was above 42.5 degrees C and maximum discharge several degrees above it. Approximately 50% of units activated by radiant heat belonged to this group. (3) Responses to radiant heat stimulation were frequently affected by a first noxious heat application. It consisted: --in a threshold decrease and/or an increase of their cellular discharge for a same temperature range. Only observed for warming/noxious heat units and noxious heat units, this sensitization phenomenon predminantly affected noxious heat units. --in a decrease of cellular discharge for a same temperature range. This desensitization phenomenon was observed for the 3 groups of units driven by radiant heat but mainly for warming units. (4) Supramaximal transcutaneous electrical stimulation revealed that nearly all the thermally sensitive units received A delta and/or C inputs. These units were largely distributed throughout the dorsal horn (laminae I, IV and V). Ten of the 12 lamina I units responded to noxious thermal stimuli. (5) These data indicate that an increase in skin temperature is coded at the level of the rat spinal cord dorsal horn by both an increase in discharge of low threshold temperature sensitive units and a progressive recruitment of high threshold units.     

Nociceptor-driven dorsal horn neurones in the lumbar spinal cord of the cat

Single dorsal horn neurones have been recorded extracellularly in the lumbar spinal cord of cats anaesthetized with chloralose. Cold block at L₁ was used to provide reversible spinalization. The location of the units in the dorsal horn was marked by the electrophoretic deposition of pontamine sky blue from the recording microelectrode. There was a clear somatotopic representation of the ventrolateral surface of the foot in the L₆ segment. Thirty-five of the 46 units recorded in the marginal zone of the L₆ dorsal horn (lamina I) could only be excited by volleys in small afferent fibres and by noxious stimulation of the skin in the foot regions and were termed class 3 cells. The remaining 11 units could, in addition, be excited by sensitive cutaneous mechanosensitive afferent units — they were class 2 units. The ‘specific’ nociceptor-driven neurones could be divided into 2 subclasses on the basis of their excitability by afferent fibres. Class 3 (a) were excited only by Aδ cutaneous afferents and class 3 (b) by both Aδ and C cutaneous afferents. Some of the latter were also excited by Aδ and C afferent fibres in the lateral gastrocnemius nerve. When tested by natural stimulation all class 3 cells were excited by noxious mechanical stimuli, but only the 3 (b) units were effectively excited by heating the skin. This discharge in 3 (b) units could be suppressed by electrical stimulation of large (group II) cutaneous myelinated afferent fibres and a similar effect could be produced in responses evoked by Aδ and C afferent volleys. Additional inhibition was accomplished by electrical stimulation of the slower myelinated cutaneous (Aδ or group III) afferent fibres. The excitability of the class 3 cells was greater in spinal preparations but the tonic descending inhibition was weaker than the apparently similar descending tonic inhibition of class 2 cells. The results are discussed with reference to pain mechanisms.     

Do convergent neurones in the spinal dorsal horn discriminate nociceptive from non-nociceptive information?

Thirty convergent neurones responding to both noxious and non-noxious cutaneous stimuli were recorded at the lumbar level in either anaesthetized 'intact' rats or unanaesthetized 'spinal' rats. Their responses to radiant heat application and to repetitive innocuous mechanical stimulation of the centre of their receptive fields were analysed, both in terms of the maximal and the mean firing rates. These neurones increased their discharge rates in relation to the temperature applied to their receptive fields with the highest levels being produced by noxious intensities. This finding confirms earlier reports suggesting the capacity of these neurones to encode nociceptive information of thermal origin. However, a very high level of firing could also be evoked by repetitively applied innocuous mechanical stimuli. This was a consistent finding, observed both in intact and spinal animals, which was true for the two subgroups into which we divided the convergent neurones (warming/noxious heat units and noxious heat units). These results are discussed in terms of the role of convergent neurones in nociception. It is suggested that a single channelled signal emanating from these neurones could not be the basis of a clear nociceptive message to the brain; two alternative hypotheses involving multichannelled organizations of impulses are proposed for discussion.     

Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurones in the rat dorsal horn

We have studied the effects of intrathecal morphine on the responses of 38 dorsal horn neurones in the intact rat under halothane anaesthesia to A and C fibre electrical stimulation and to natural stimuli applied to their receptive fields. Morphine selectively reduced the C fibre and pinch evoked activity in a dose-dependent naloxone-reversible manner with an ED50 of 7 nmoles. The 'wind-up' of neurones to repetitive stimulation was little altered except with the highest doses (50-150 nmoles) tested. By contrast, the A fibre evoked responses of the neurones were only slightly reduced by morphine and both the tactile responses and receptive field size to innocuous stimuli enhanced for certain cells. The results are discussed in relation to the spinal actions of opiates and their clinical applications.     

Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain

Cancer-induced bone pain is a major clinical problem. A rat model based on intra-tibial injection of MRMT-1 mammary tumour cells was used to mimic progressive cancer-induced bone pain. At the time of stable behavioural changes (decreased thresholds to mechanical and cold stimuli) and bone destruction, in vivo electrophysiology was used to characterize natural (mechanical, thermal, and cold) and electrical-evoked responses of superficial and deep dorsal horn neurones in halothane-anaesthetized rats. Receptive field size was significantly enlarged for superficial neurones in the MRMT-1 animals. Superficial cells were characterised as either nociceptive specific (NS) or wide dynamic range (WDR). The ratio of WDR to NS cells was substantially different between sham operated (growth media alone) (26:74%) and MRMT-1 injected rats (47:53%). NS cells showed no significant difference in their neuronal responses in MRMT-1-injected compared to sham rats. However, superficial WDR neurones in MRMT-1-injected rats had significantly increased responses to mechanical, thermal and electrical (A beta-, C fibre-, and post-discharge evoked response) stimuli. Deep WDR neurones showed less pronounced changes to the superficial dorsal horn, however, the response to thermal and electrical stimuli, but not mechanical, were significantly increased in the MRMT-1-injected rats. In conclusion, the spinal cord is significantly hyperexcitable with previously superficial NS cells becoming responsive to wide-dynamic range stimuli possibly driving this plasticity via ascending and descending facilitatory pathways. The alterations in superficial dorsal horn neurones have not been reported in neuropathy or inflammation adding to the evidence for cancer-induced bone pain reflecting a unique pain state.     

Reciprocal connections between the medullary dorsal reticular nucleus and the spinal dorsal horn in the rat

The synaptic architecture of spinal afferents of the dorsal portion (DRtd) of the medullary dorsal reticular nucleus (DRt) is studied. After iontophoretic injections of cholera toxin subunit B (CTb) into the superficial (laminae I-II), deep (laminae IV-V) or entire (laminae I-V) dorso-ventral extent of the spinal dorsal horn at the cervico-thoracic or lumbo-sacral levels, axonal boutons of two distinct types were labelled in the DRtd. Type A boutons (82% after cervico-thoracic injections and 92% after lumbo-sacral injections) were roundish, small and presented few mitochondria and small, round synaptic vesicles. Type B boutons (18% after cervico-thoracic injections and 8% after lumbo-sacral injections) were elongated, two to three times larger, and exhibited numerous mitochondria and larger round vesicles. Both types of bouton established asymmetrical synaptic contacts with small dendritic profiles and, less frequently, with dendritic trunks and perikarya. Retrograde labelling occurred in the postsynaptic profile of 15-18% type A boutons labelled from any injection site. Taken together with previous data on DRt-spinal synaptic contacts at the superficial dorsal horn, the present results point to the occurrence of a reciprocal excitatory loop connecting the dorsal DRt and lamina I, which may be at the basis of the DRt-mediated pain-facilitating effects described recently.     

A block of spinal nitric oxide synthesis leads to increased background activity predominantly in nociceptive dorsal horn neurones in the rat

Previous studies have shown that nitric oxide (NO) has a strong influence on the background (resting) activity of dorsal horn neurones. The background activity of dorsal horn neurones is generally assumed to be responsible for the presence of paraesthesia or spontaneous pain in patients depending on the functional type of neurones that are active. However, nothing is known about a possible selective action of NO - or a lack of NO - on a particular functional class of neurone. In the present study the background activity of lumbar dorsal horn neurones was examined in anaesthetized rats before and during spinal superfusion with L-NAME, an unspecific blocker of NO synthesis. The neurones were divided into five classes: (1) low-threshold mechanosensitive (LTM) cells with deep receptive fields (LTM deep units); (2) LTM cells with cutaneous receptive fields (LTM cutaneous units) (these two classes were considered to be non-nociceptive); (3) high-threshold mechanosensitive (HTM) deep cells; (4) HTM cutaneous cells; and (5) multireceptive (MR) cutaneous cells (the last three classes were assumed to be nociceptive). HTM neurones increased the frequency of their background activity significantly during L-NAME superfusion and 80% of the initially silent neurones became active after administration of the NOS blocker. MR neurones likewise increased their background activity. In contrast, the background activity of non-nociceptive (LTM) neurones was not significantly affected. The results support previous studies showing that NO has a tonic depressing effect on the background activity of dorsal horn neurones and demonstrate for the first time that this effect is largely restricted to nociceptive neurones. Therefore, a reduction in spinal NO synthesis which often occurs during a long-lasting peripheral lesion is likely to cause increased background activity in nociceptive neurones and thus might contribute to spontaneous pain in patients.     

Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy

Selective ligation of the L5/L6 spinal nerves produces a partial denervation of the hindpaw and has proved to be a useful model for studying the mechanisms underlying neuropathic pain. Two weeks after surgery, in vivo electrophysiological studies were performed in sham operated and nerve injured rats and the responses of spinal dorsal horn neurones to controlled electrical and natural (mechanical and heat) stimuli were recorded. The systemic effects of three N-methyl-D-aspartate receptor (NMDA) antagonists, ketamine (1-10 mg/kg), memantine (1-20 mg/kg) and MK-801 (0.1-5 mg/kg) were compared. Ketamine a clinically available NMDA receptor antagonist, produced greater reductions of the postdischarge, thermal (10 mg/kg, P=0.02), and mechanical evoked responses in spinal nerve ligated (SNL) rats (von Frey 9 g, 1 mg/kg, P=0.04; 5 mg/kg, P=0.01; 10 mg/kg, P=0.05; von Frey 50 g, 5 mg/kg, P=0.02; 10 mg/kg, P=0.003). The inhibition of wind-up was comparable in both animal groups. Memantine produced powerful inhibitions of wind-up after nerve injury with little effect in sham controls (5 mg/kg, P=0.02). The postdischarge, mechanical and thermal evoked responses were reduced to similar extents by memantine in both experimental groups. The effects of MK-801 were comparable between SNL and sham operated rats for all neuronal measures (wind-up, postdischarge, thermal and noxious mechanical evoked responses). The differential blocking abilities of these antagonists on the various neuronal responses may relate to the characteristics of their voltage-dependent blockage of the channel associated with the receptor. The favourable side effect profile of memantine supports its potential use for the treatment of neuropathic pain.     

Tonic descending inhibition affects intensity coding of nociceptive responses of spinal dorsal horn neurones in the cat

The supraspinal inhibitory control of lumbar spinal dorsal horn neurones was investigated in N2O-anaesthetized cats by reversibly blocking conduction in the spinal cord. Dorsal horn neurones selected for this study had convergent input from myelinated (A-) and unmyelinated (C-) fibres in the posterior tibial and/or superficial peroneal nerves of the hind limb. Virtually all of them could also be excited by noxious heating of the skin of the footpad region and by low intensity mechanical stimulation of the foot. Variation of the temperature of noxious radiant skin heating (40-56 degrees C, 10 sec in duration) resulted in graded responses of the neurones. The stimulus-response functions (SRF) were monotonic; in the majority of 32 cases they were linear. Neurones could be classified according to their maximum discharge frequency in response to skin heating into 22 weakly sensitive units (responses below 100 Hz at 50 degrees C) and 10 highly sensitive units (above 100 Hz). Responses outlasted the period of skin heating by seconds to minutes. A reversible conduction block of spinal axons by cooling a 15 mm cord segment (L1) with a thermode at 0 degrees C affected the responsiveness of the dorsal horn neurones in 12 of 15 cases. The maximum discharge frequency to a certain temperature of skin heating was increased during the spinal block. The duration of heat-evoked discharges was either not changed or increased during the spinal block. The SRF were reversibly displaced during the spinal blockade to higher discharge frequencies and lower threshold temperatures of skin heating. In 8 of 12 cases the change in the SRF was a nearly parallel shift, whereas in 4 units the increase of responsiveness had a complex effect upon the SRF. The decrease in the threshold to skin heating ranged up to 4.5 degrees C; the mean decrease was 2 degrees C. It is confirmed that in anaesthetized cats, nociceptive spinal neurones are subject to a tonically active descending inhibition, which is interrupted by local spinal cooling. The effect of the spinal block on the SRF of the neurones suggests that this tonic inhibition is similar to that produced by electrical stimulation in the lateral reticular formation of the brain-stem.     

Effects of tizanidine (DS 103-282) on dorsal horn convergent neurones in the rat

The effects of tizanidine, a new muscle relaxant, 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiazole (DS 103-282) were studied on the activity of lumbar dorsal horn convergent neurons in anaesthetized paralysed rats. Following i.v. administration of tizanidine both the A- and C-fibre evoked responses were depressed in a dose-dependent manner in the 0.125-1.0 mg/kg range. The smaller dose employed (0.125 mg/kg) induced a significant depression of the C-fibre evoked responses (39.6 +/- 13.4% of the control responses) and a total recovery was observed 10 min after the injection: when the doses were increased, stronger and longer-lasting depressant effects were obtained. Identical but less powerful effects were observed on A-fibre responses. None of the depressive effects was correlated with variations in blood pressure. Microelectrophoretically applied tizanidine was found to depress current-dependently, the discharges of convergent neurones evoked by microelectrophoretically applied DL-homocysteic acid. In contrast, tizanidine (0.5, 1 mg/kg; i.v.) was found to be ineffective against the activities of non-nociceptive neurones triggered by mechanical stimulation of their receptive fields. It is concluded that tizanidine depresses specifically the activities of dorsal horn convergent neurones, probably in part by a post-synaptic inhibitory action. Owing to the role of convergent neurones in pain processes, the present result could explain, at least partially, the analgesic action of this compound.     

大鼠脊髓背角TRPV4在背根神经节持续受压致神经病理性疼痛中的作用

目的:探讨大鼠背根神经节(dorsal root ganglion,DRG)持续受压(chronic compression of right side dorsal root ganglion,CCD)后脊髓背角瞬时感受器电位离子通道4(TRPV4)基因及蛋白变化,明确脊髓背角TRPV4在CCD致神经病理性疼痛中的作用。方法:采用健康成年雄性Wistar大鼠,共36只,随机分为3组,分别为空白对照组、CCD手术组、CCD+钌红组。制备大鼠背根神经节持续受压模型,于术前1天、术后第7天、给药前及给药2h后,测量大鼠机械刺激缩爪反应阈值,观察机械痛阈的变化;利用RT-PCR及Western Blot技术检测各组大鼠手术侧脊髓背角TRPV4基因及蛋白表达的变化。结果:与空白对照组相比,术后第7天,CCD组大鼠术侧机械痛阈值明显下降(P0.001),同侧脊髓背角TRPV4基因及蛋白表达升高(P0.05);与给药前相比,给予钌红2h后,术侧机械痛阈值明显升高(P0.001),同侧脊髓背角TRPV4基因及蛋白表达下降(P0.05)。结论:CCD后大鼠术侧机械痛阈下降,脊髓背角TRPV4基因及蛋白表达升高;钌红可部分逆转CCD后痛觉过敏,部分降低脊髓背角TRPV4基因及蛋白表达。脊髓背角TRPV4参与CCD后大鼠神经病理性疼痛形成。     

Altered effects of an A1 adenosine receptor agonist on the evoked responses of spinal dorsal horn neurones in a rat model of mononeuropathy

There is clinical evidence that adenosine might be a useful treatment for neuropathic pain states, although little is known regarding its mechanisms. In this study, we use the selective (L5/L6) spinal nerve ligation model to investigate the effects of an adenosine A₁ receptor agonist, N⁶-cyclopentyladenosine (CPA), on the evoked responses of dorsal horn neurones after nerve injury in vivo. Two weeks after surgery, the responses of dorsal horn neurones to controlled electrical and natural (mechanical and thermal) stimuli were recorded and the effects of intrathecal CPA were compared between nerve-ligated and sham-operated rats. CPA produced significant inhibitions of the C-fiber—evoked response, postdischarge, wind-up, mechanical, and thermal-evoked responses in both groups, but only minor inhibitions of the Aβ-fiber response. Overall, the drug effects in spinal nerve-ligated rats were greater than those of sham-operated rats. Spinal theophylline reversed these inhibitions. In contrast, CPA produced marked facilitations of the Aδ-fiber—evoked neuronal responses in sham-operated animals, yet this effect was completely absent after nerve injury. These results suggest that nerve injury induces plasticity in the spinal A₁ receptor system, which might form the basis for the therapeutic use of adenosine.     

The stereospecific effect of naloxone on rat dorsal horn neurones; Inhibition in superficial laminae and excitation in deeper laminae

The effect of systemic naloxone on the activity evoked by C-fibre stimulation in dorsal horn neurones of the rat spinal cord has been investigated. Recordings were made in unanaesthetized, decerebrate spinalized rats. Fifteen units were recorded from laminae 4 and 5 of the dorsal horn, 11 of these units were excited by naloxone (0.2–1.0 mg/kg). The onset of this excitation was after 20 sec to 5 min and recovery to control levels occurred within 15–40 min. Of 17 units recorded in substantia gelatinosa of the dorsal horn, 13 were inhibited by the naloxone. The latency of onset of this inhibition was short (2–10 sec) and the effect persisted for 5–10 min. The effects were largely restricted to C-fibre evoked activity although sometimes Aδ responses were similarly altered. Neurones stimulated at Aβ-fibre threshold, or whose sole afferent input were Aβ-fibres, were unaffected by the naloxone. The stereoisomer of naloxone, (+)naloxone which is inactive in opiate receptor binding tests, failed to produce the same changes found with (?)naloxone in 17 units. These results show a differential effect of naloxone on neurones in the dorsal horn which respond to C-fibre input. Units in the substantia gelatinosa are inhibited while units in deeper laminae are excited by naloxone. These effects are likely to be mediated by the blockade of endogenous opioids in the spinal cord.     

The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain

The treatment of pain arising from nerve injury can be difficult and the opioid sensitivity of neuropathic pain remains debatable. Clinical and animal studies report a wide range in the effectiveness of morphine, ranging from inadequate to potent analgesia. In this electrophysiological study we compare the effectiveness of spinal versus systemic administration of morphine on the natural and electrically evoked responses of spinal neurones of rats with a selective spinal nerve (L5/6) ligation. Recordings were made 1 week and/or 2 weeks after ligation. We have also compared the effects of morphine, by the two routes, on normal and sham operated animals. In spinal nerve ligated rats, morphine (0.1-5 microg) administered via the intrathecal route produced greater dose-dependent inhibitions of the neuronal responses compared with those produced by the systemic route (1-6 mg/kg). The dose response curves for intrathecal morphine on the C-fibre evoked and noxious natural stimuli evoked neuronal responses (mechanical and thermal) of spinal nerve ligated rats were to the left of those of sham operated and normal rats, suggesting an enhanced potency of intrathecal morphine after nerve injury. This was clearest for the lower doses of the opioid. The effects of spinal morphine on the responses to low intensity stimuli were similar in all groups of rats. In contrast to the spinal route, systemic morphine was less effective in inhibiting the evoked neuronal responses of spinal nerve ligated rats. This was especially clear for the C-fibre evoked and noxious natural stimuli evoked responses (mechanical and thermal) of spine nerve ligated rats. Our results suggest that the effectiveness of morphine may be partly related to the timing of the treatment relative to the duration of the neuropathy, the route of administration and also the neuropathic symptom. Spinal opioids may be a useful approach to pain control in neuropathic pain states where systemic routes produce inadequate analgesia.     

Differential responses of nociceptive vs. non-nociceptive spinal dorsal horn neurones to cutaneously applied vibration in the cat

Extracellular single-unit recordings were made from dorsal horn neurones in the lumbar spinal cord of cats which were anaesthetized or were anaemically decerebrated. Each neurone was classified functionally as wide dynamic range (WDR), non-nociceptive, nociceptive specific or proprioceptive. Vibration was then applied to the hind limb using a feedback-controlled mechanical stimulator.

WDR neurones had 3 distinct types of response to vibration (80 Hz; 0.3–1.0 mm): excitation, depression and a biphasic response consisting of excitation followed by depression [16]. The type of response depended upon the location of the stimulator probe. With the stimulator probe placed inside that part of the receptive field from which low intensity, non-vibrational cutaneous stimuli elicited excitation, 35 neurones were excited by the vibratory stimulation, none was depressed and 4 showed the biphasic response. On the other hand, when the probe was positioned outside the receptive field for low intensity stimuli, 7 WDR neurones were excited, 164 showed depression or the biphasic response and 7 were unaffected. On-going activity and activity evoked by iontophoretic application of glutamate were decreased during the depressant response and during the depressant phase of the biphasic response.

In terms of non-nociceptive neurones, all (n = 30) were excited by vibration; depressant or biphasic responses were not observed. Excitation was elicited by placing the probe either inside or outside the receptive field for non-vibrational stimuli.

All nociceptive specific neurones (n = 3) were depressed by vibration regardless of the position of the stimulus. All proprioceptive neurones (n = 12) were excited by vibration.

The predominantly depressant effect of vibration on nociceptive neurones vs. the predominantly excitatory effect on non-nociceptive neurones prompts us to suggest that the increase in pain threshold and the clinical analgesia elicited by vibration may be mediated at the spinal level by a decrease in the rate of firing of nociceptive neurones and/or by excitation of non-nociceptive neurones.     

Electrophysiological characterisations of rat lamina I dorsal horn neurones and the involvement of excitatory amino acid receptors

Lamina I of the spinal cord plays a key role in sensory transmission between afferent activity and the CNS. Studies have shown lamina I neurones to have distinct response properties compared to deep dorsal horn neurones, but little is known regarding excitatory amino acid mechanisms in their responses. Spinal electrophysiological recordings of lamina I neurones confirmed that the majority of these neurones (74%) are nociceptive specific (NS) in their responses, of which 18% can be termed polymodal nociceptive (HPC) (13% of the total population). The remainder (26%) were wide dynamic range. Lamina I neurones had smaller mechanical and heat-evoked responses compared to deeper dorsal horn neurones. The electrically evoked responses were also smaller, with a distinct lack of an NMDA-mediated 'wind-up' effect. NBQX (AMPA receptor antagonist, 0.5, 5, 50 microg/50 microl) produced dose-dependent inhibitions of the electrically evoked neuronal responses, but APV (NMDA receptor antagonist, 50, 100, 500 microg/50 microl) had minimal effects on their responses. These results implicate mainly AMPA receptors in the responses of lamina I neurones. Bicuculline (GABA(A) receptor antagonist, 0.5, 5, 50 microg/50 microl) demonstrated a role exerted by GABA(A) receptors in the control of A-delta fibre-mediated mechanical responses in lamina I. Overall, this study describes a high threshold, AMPA receptor possessing population of lamina I neurones, which seem to lack functional NMDA receptors, and are partially controlled by GABA(A) receptor activity.     

Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.

(1) Sixty-eight convergent dorsal horn neurones have been recorded at the lumbar level in anaesthetized intact rats. All cells received prominent A alpha and C fibre afferents and correspondingly could be activated by high and low threshold stimuli applied to the peripheral excitatory receptive field. (2) The activity of 67/68 of these neurones was powerfully inhibited by noxious stimuli applied to various parts of the body. Since non-noxious stimuli were ineffective in this respect, the term "diffuse noxious inhibitory controls" (DNIC) is proposed. (3) DNIC could be evoked by noxious pinch applied to the tail, the contralateral hind paw, the forepaws, the ears and the muzzle; the most effective areas were the tail and muzzle. Noxious heat applied to and transcutaneous electrical stimulation of the tail were extemely effective in eliciting DNIC as was the intraperitoneal injection of bradykinin. (4) DNIC strongly depressed by 60-100% both the C fibre response following suprathreshold transcutaneous electrical stimulation and the responses to noxious radiant heat. (5) The spontaneous activity and the responses to low threshold afferents induced either by A alpha threshold electrical or natural stimulation were also powerfully inhibited. (6) In the majority of cases, long lasting post-effects directly related to the duration of conditioning painful stimulus were observed.     

Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn

In order to understand how nociceptive information is processed in the spinal dorsal horn we need to unravel the complex synaptic circuits involving interneurons, which constitute the vast majority of the neurons in laminae I–III. The main limitation has been the difficulty in defining functional populations among these cells. We have recently identified 4 non-overlapping classes of inhibitory interneuron, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) and parvalbumin, in the rat spinal cord. In this study we demonstrate that these form distinct functional populations that differ in terms of sst_2A receptor expression and in their responses to painful stimulation. The sst_2A receptor was expressed by nearly all of the nNOS- and galanin-containing inhibitory interneurons but by few of those with NPY and none of the parvalbumin cells. Many galanin- and NPY-containing cells exhibited phosphorylated extracellular signal-regulated kinases (pERK) after mechanical, thermal or chemical noxious stimuli, but very few nNOS-containing cells expressed pERK after any of these stimuli. However, many nNOS-positive inhibitory interneurons up-regulated Fos after noxious thermal stimulation or injection of formalin, but not after capsaicin injection. Parvalbumin cells did not express either activity-dependent marker following any of these stimuli. These results suggest that interneurons belonging to the NPY, nNOS and galanin populations are involved in attenuating pain, and for NPY and nNOS cells this is likely to result from direct inhibition of nociceptive projection neurons. They also suggest that the nociceptive inputs to the nNOS cells differ from those to the galanin and NPY populations.