Responses Of Dorsal Horn Neurons Research Articles

Colonic mechanoreceptor inputs to rat lumbo-sacral dorsal horn neurones: distribution, thresholds and chemosensory modulation.

In order to better understand the central processing of visceral sensory information, we studied the responses of lumbo-sacral dorsal horn (L4-S1) neurones to colonic stimuli in anaesthetized rats. Twenty-four neurones responded to distal colonic distension with a 2.5-cm balloon; six of these were tested with proximal colonic distension, to which none responded. All neurones tested responded to somatic non-noxious inputs (tail movement). Responses to colonic distension were excitatory (n=22) or inhibitory (n=2). Sixteen neurones responded at a threshold of 20 mmHg or less, five at 20-40 mmHg, and three at 40-80 mmHg. Three of 10 neurones tested showed increased responses to colonic distension after intraluminal perfusion with bile. Bile itself did not evoke a response. We conclude that lumbo-sacral spinal neurones selectively receive mechanosensory inputs from the distal colon. Neurones respond at thresholds within and above the physiological range. Dorsal horn neurones receiving colonic mechanosensory inputs are not directly modulated by chemosensory inputs, but their responsiveness to distension may be augmented.

Enhanced responses of spinal dorsal horn neurons to heat and cold stimuli following mild freeze injury to the skin.

The effects of a mild freeze injury to the skin on responses of nociceptive dorsal horn neurons to cold and heat stimuli were examined in anesthetized rats. Electrophysiological recordings were obtained from 72 nociceptive spinal neurons located in the superficial and deep dorsal horn. All neurons had receptive fields (RFs) on the glabrous skin of the hindpaw, and neurons were functionally divided into wide dynamic range (WDR) and high-threshold (HT) neurons. Forty-four neurons (61%) were classified as WDR and responded to both innocuous and noxious mechanical stimuli (mean mechanical threshold of 12.8 +/- 1.6 mN). Twenty-eight neurons (39%) were classified as HT and were excited only by noxious mechanical stimuli (mean mechanical threshold of 154.2 +/- 18.3 mN). Neurons were characterized for their sensitivity heat (35 to 51 degrees C) and cold (28 to -12 degrees C) stimuli applied to their RF. Among WDR neurons, 86% were excited by both noxious heat and cold stimuli, while 14% responded only to heat. For HT neurons, 61% responded to heat and cold stimuli, 32% responded only to noxious heat, and 7% responded only to noxious cold. Effects of a mild freeze injury (-15 degrees C applied to the RF for 20 s) on responses to heat and cold stimuli were examined in 30 WDR and 22 HT neurons. Skin freezing was verified as an abrupt increase in skin temperature at the site of injury due to the exothermic reaction associated with crystallization. Freezing produced a decrease in response thresholds to heat and cold stimuli in most WDR and HT neurons. WDR and HT neurons exhibited a mean decrease in response threshold for cold of 9.0 +/- 1.3 degrees C and 10.0 +/- 1.6 degrees C, respectively. Mean response thresholds for heat decreased 4.0 +/- 0.4 degrees C and 4.3 +/- 1.3 degrees C in WDR and HT neurons, respectively. In addition, responses to suprathreshold cold and heat stimuli increased. WDR and HT neurons exhibited an 89% and a 192% increase in response across all cold stimuli, and a 93 and 92% increase in responses evoked across all heat stimuli, respectively. Our results demonstrate that many spinal neurons encode intensity of noxious cold as well as noxious heat over a broad range of stimulus temperatures. Enhanced responses of WDR and HT neurons to cold and heat stimuli after a mild freeze injury is likely to contribute to thermal hyperalgesia following a similar freeze injury in humans.

Peripheral inflammation reduces the response of spinal dorsal horn neurons to an NK3 receptor agonist

The neurokinin receptors NK1 and NK3 are involved in processing nociceptive information in the spinal dorsal horn and in central changes following persistent peripheral injury. However, little is known about functional changes in these receptor systems, particularly the NK3 receptor. We have performed intracellular recordings from spinal dorsal horn neurons in vitro, using spinal cords obtained both from control rats and from those with a peripheral inflammation induced by carrageenan. Application of the NK1 receptor agonist, [Sar 9, Met(O 2) 11]Substance P and the NK3 receptor agonist, Senktide, produced slow, long lasting depolarizations. The Senktide- but not [Sar 9, Met(O 2) 11]Substance P-induced depolarizations were significantly smaller in carrageenan-treated rats. These data indicate an altered role for the NK3 receptor in the spinal dorsal horn following acute peripheral inflammation.

Thiopental directly depresses lumbar dorsal horn neuronal responses to noxious mechanical stimulation in goats.

Thiopental has hypnotic actions in the brain, but it also depresses nociceptive transmission. In this study we examined whether thiopental had direct (spinal) and/or indirect (supraspinal) effects on the responses of single lumbar dorsal horn neurons to noxious mechanical stimulation, using a method to deliver thiopental differentially to either the torso or cranial circulation in goats. Goats (n=10) were anesthetized with isoflurane and neck dissections performed to permit cranial bypass. A lumbar laminectomy was made to permit single-unit recording of lumbar dorsal horn neuronal activity (1-2 neurons/animal). Isoflurane was maintained at 0.8+/-0.1% to both head and torso throughout the study. During cranial bypass, thiopental was separately administered to the torso (low dose, 1.5+/-0.5 mg/kg; high dose, 3.7+/-0.5 mg/kg) or cranial (low dose, 0.12+/-0.03 mg/kg; high dose, 0.2 mg/kg) circulation. Thiopental administered to the torso significantly depressed dorsal horn neuronal responses to noxious stimulation at the high dose: 757+/-471 to 392+/-305 impulses/min at 1 min post-injection, P<0.006 (n=14); evoked responses recovered at 5 min post-injection. At the low dose, there was a similar numerical decrease, but this did not reach significance: 876+/-780 to 407+/-499 impulses/min at 1 min post-injection, P>0.05 (n=6). No significant change was observed when thiopental was administered to the cranial circulation: low dose, 1061+/-1167 to 965+/-874 impulses/min at 1 min post-injection, P>0.05 (n=10); high dose, 864+/-331 to 917+/-525 impulses/min at 1 min post-injection, P>0.05 (n=8). Thiopental has a direct (spinal) depressant effect on dorsal neuronal responses to noxious stimulus, but no significant supraspinal effect.

Metabotropic Glutamate Receptor Subtypes 1 and 5 Are Activators of Extracellular Signal-Regulated Kinase Signaling Required for Inflammatory Pain in Mice

Metabotropic glutamate receptors are expressed abundantly in the spinal cord and have been shown to play important roles in the modulation of nociceptive transmission and plasticity. Most previous studies have focused on the group I metabotropic glutamate receptors (mGluR1 and mGluR5) and activation of phospholipase C signaling by these receptors in modulating nociception. Recently, it was shown that the extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases are activated in spinal cord dorsal horn neurons in response to stimulation of nociceptors and that ERK signaling is involved in nociceptive plasticity. In the present studies, we sought to test the hypothesis that group I mGluRs modulate nociceptive transmission or plasticity via modulation of ERK signaling in dorsal horn neurons. We show that activation of mGluR1 and mGluR5 leads to activation of ERK1 and ERK2 in the spinal cord. Furthermore, we find that inflammation-evoked ERK activation, which is required for nociceptive plasticity, is downstream of mGluR1 and mGluR5. Finally, we show colocalization of group I mGluRs with activated ERK in dorsal horn neurons. These results show that mGluR1 and mGluR5 are activated in dorsal horn neurons in response to peripheral inflammation and that activation of these group I mGluRs leads to activation of ERK1 and ERK2, resulting in enhanced pain sensitivity.

Meloxicam selectively depresses the afterdischarge of rat spinal dorsal horn neurones in response to noxious stimulation

This study examined the effects of the cyclooxygenase-2 (COX-2) inhibitor, meloxicam, on responses of spinal dorsal horn neurones to synaptic inputs in vivo. Experiments were run using male Sprague–Dawley rats (350–375 g) anesthetized with Na-pentobarbital (50 mg/kg, i.p.) and acutely spinalized at T9. Spinal segments L1–4 were exposed for extracellular single unit recording of on-going and stimulation-evoked activity of eight wide dynamic range neurones. On-going activity was unaffected by meloxicam (0.1 mg/kg, i.v.). However, responses to noxious mechanical stimulation (21 N for 3 s) of the cutaneous receptive field of the hind paw were depressed by meloxicam in particular the afterdischarge (34.50±6.06% inhibition) in all eight neurones studied. The brief initial discharge in response to stimulation was depressed less (15.31±4.89% inhibition, n=7/8). The data indicate that the percent inhibition of the afterdischarge was significantly greater than that of the initial discharge ( P<0.05). Given the selectivity of meloxicam for COX-2, the data suggest that COX-2 may be involved in mediating and/or modulating excitatory effects of nociceptive inputs to dorsal horn neurones, in particular the prolonged stimulation-evoked afterdischarge.

Modulation of pain by [1DMe]NPYF, a stable analogue of neuropeptide FF, in neuropathic rats

The pain modulatory effects of ( d-Tyr) l(Me-Phe)QPQRF-amide ([1DMe]NPYF), a stable analogue of neuropeptide FF were studied in rats with a chronic neuropathy induced by unilateral ligation of two spinal nerves. According to behavioral assessments, intrathecal (i.t.) administration of [1DMe]NPYF induced mechanical antiallodynic and thermal antinociceptive effects in a parallel and dose-dependent fashion, whereas following administration in the periaqueductal gray (PAG) it produced only mechanical antiallodynia. I.t. or PAG administration of FLFQPQRF, a non-amidated form of NPFF, or intraplantar injection of [1DMe]NPYF into the neuropathic paw had no effects. Electrophysiological results indicated that administration of [1DMe]NPYF suppressed responses of nociceptive spinal dorsal horn neurons in a submodality selective way and without an effect on their spontaneous activity; PAG administration predominantly suppressed brush-evoked responses and i.t. administration heat-evoked responses. The descending inhibitory effect by conditioning electrical stimulation of the PAG was enhanced by i.t. administration of [1DMe]NPYF. The reversibility of [1DMe]NPYF-induced effects by naloxone (1 mg/kg subcutaneously) depended on the submodality of test stimulation and the route of drug administration. The amplitude of the innocuous H-reflex was not changed by [1DMe]NPYF administered i.t. in control rats. The present results indicate that [1DMe]NPYF produces a selective attenuation of pain in neuropathic animals due to naloxone-sensitive or -insensitive central mechanisms depending on the submodality of pain and route of drug administration. The amide-group is essential for the [1DMe]NPYF-induced attenuation of pain.

Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy

Neuropathic pain, due to peripheral nerve damage, can include allodynia (perception of innocuous stimuli as being painful), hyperalgesia (increased sensitivity to noxious stimuli) and spontaneous pain, often accompanied by sensory deficits. Plasticity in transmission and modulatory systems are implicated in the underlying mechanisms. The Kim and Chung rodent model of neuropathy (Kim and Chung, Pain 50 (1992) 355) employed here involves unilateral tight ligation of two (L5 and L6) of the three (L4, L5, and L6) spinal nerves of the sciatic nerve and reproducibly induced mechanical and cold allodynia in the ipsilateral hindpaw over the 14 day post-operative period. In vivo electrophysiological techniques have then been used to record the response of dorsal horn neurones to innocuous and noxious electrical and natural (mechanical and thermal) stimuli after spinal nerve ligation (SNL). Activation of voltage-dependent calcium channels (VDCCs) is critical for neurotransmitter release and neuronal excitability, and antagonists can be antinociceptive. Here, for the first time, the effect of N- and P-type VDCC antagonists (ω-conotoxin-GVIA and ω-agatoxin-IVA, respectively) on the evoked dorsal horn neuronal responses after neuropathy have been investigated. Spinal ω-conotoxin-GVIA (0.1–3.2 μg) produced prolonged inhibitions of both the electrically- and low- and high-intensity naturally-evoked neuronal responses in SNL and control rats. Spinal ω-agatoxin-IVA (0.1–3.2 μg) also had an inhibitory effect but to a lesser extent. After neuropathy the potency of ω-conotoxin-GVIA was increased at lower doses in comparison to control. This indicates an altered role for N-type but not P-type VDCCs in sensory transmission after neuropathy and selective plasticity in these channels after nerve injury. Both pre- and post-synaptic VDCCs appear to be important.

The effect of ABT‐702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury

1. Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside adenosine kinase (AK) inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT-702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain. 2. Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously following either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. 3. ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evoked responses in both carrageenan and nerve-injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT-702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance. 4. Protection of endogenous adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous adenosine-mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states.

Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat.

Spinal cord slices and whole-cell patch clamp recordings were used to investigate the effects of serotonergic receptor ligands on dorsal root-evoked synaptic responses in deep dorsal horn (DDH) neurons of the neonatal rat at postnatal days (P) 3 - 6 and P10 - 14. Bath applied 5-hydroxytryptamine (5-HT) potently depressed synaptic responses in most neurons. Similarly, the 5-HT(1/7) receptor agonist, 5-carboxamidotryptamine (5-CT) depressed synaptic responses. This action was probably mediated by 5-HT(1A) receptor activation, since it occurred in the presence of the 5-HT(7) receptor antagonist clozapine and was not observed in the presence of NAN-190, a 5-HT(1A) receptor antagonist. In the absence of any agonist, 5-HT(1A) receptor antagonists often facilitated synaptic responses, suggesting that there is sufficient endogenous 5-HT to tonically activate 5-HT(1A) receptors. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the 5-HT(1A/7) receptor agonist, facilitated synaptic responses, an action probably mediated by 5-HT(7) receptors, since the facilitation could be reversed by subsequent application of the 5-HT(7) receptor antagonist clozapine. Agonists for the 5-HT(1B), 5-HT(2) and 5-HT(3) receptors exerted only modest modulatory actions. A pharmacological analysis of the depression evoked by 5-HT suggested an action partly mediated by 5-HT(1A) receptor activation, since antagonism of the 5-HT(1A) receptor with NAN-190 or WAY-100635 partly reversed 5-HT-evoked depression. In comparison, 5-HT(7) receptor activation could account for much of the 5-HT-evoked facilitation. We conclude that 5-HT is capable of modulating sensory input onto DDH neurons via several receptor subtypes, producing both facilitatory and depressant actions. Also, the actions of most receptor ligands on the evoked responses were similar within the first 2 postnatal weeks.

Inflammation enhances reflex and spinal neuron responses to noxious visceral stimulation in rats.

To improve understanding of sensory processes related to visceral inflammation, the effect of turpentine-induced inflammation on reflex (cardiovascular/visceromotor) and extracellularly recorded lumbosacral dorsal horn neuron responses to colorectal distension (CRD) was investigated. A 25% solution of turpentine, applied to the colorectal mucosa, produced inflammation, decreased compliance of the colonic wall, and enhanced reflex responses in unanesthetized rats within 2-6 h. At 24 h posttreatment, pressor responses to CRD (80 mmHg, 20 s) were 20% greater, and intraluminal pressures needed to evoke visceromotor reflexes were 30% lower than controls. Parallel electrophysiological experiments in spinal cord-transected, decerebrate rats demonstrated that two neuronal subgroups excited by CRD were differentially affected by turpentine administered 24 h before testing. During CRD, abrupt neurons were 70% less active and sustained neurons were 25% more active than similar neurons in controls. In summary, reflex and neuronal subgroup (sustained neurons) responses to CRD were both potentiated by chemical inflammation. This suggests that the neurophysiological basis for inflammation-induced increases in reflex responses to CRD is increased activity of this neuronal subgroup.

Reduction in inflammation-induced sensitization of dorsal horn neurons by transcutaneous electrical nerve stimulation in anesthetized rats.

Transcutaneous electrical nerve stimulation (TENS) is utilized to treat a variety of painful conditions. Inflamed animals present with an increased response to noxious stimuli, i.e., hyperalgesia, at the site of injury (primary hyperalgesia) and outside the site of injury (secondary hyperalgesia). Further, following acute inflammation, dorsal horn neurons show an increased responsiveness to peripherally applied stimuli, which has been termed sensitization. Previous studies demonstrate a reduction in dorsal horn neuron activity following TENS treatment in normal animals and a reduction in primary and secondary hyperalgesia in acutely inflamed animals. The purpose of this study was to examine the effects of TENS on dorsal horn neurons sensitized by acute inflammation. Extracellular recordings from wide dynamic range (WDR), high threshold (HT) and low threshold (LT) dorsal horn neurons in anesthetized rats were assessed for spontaneous activity, responses to innocuous and noxious mechanical stimulation and receptive field size. Responses were measured before and 3 h after induction of inflammation, and immediately and 1 h after application of either high (100 Hz) or low (4 Hz) frequency TENS (motor intensity, pulse duration = 100 microseconds). TENS was applied to the inflamed paw to encompass the receptive field of the neuron for 20 min. WDR and HT dorsal horn neurons sensitized to mechanical stimulation after induction of inflammation. Application of either high or low frequency TENS to the inflamed paw reduced both innocuous and noxious evoked responses of WDR and HT dorsal horn neurons immediately and 1 h after treatment with TENS. Comparison of responses after TENS with baseline responses showed that the evoked responses in the majority of WDR and HT cells returned to or fell below baseline responses. TENS had no effect on responses of LT neurons. In summary, central neuron sensitization is reduced by TENS and may underlie the reduction in hyperalgesia observed after treatment with TENS.

Effects of ethosuximide, a T-type Ca 2+ channel blocker, on dorsal horn neuronal responses in rats

Plasticity in transmission and modulatory systems are implicated in mechanisms of neuropathic pain. Studies demonstrate the importance of high voltage-activated Ca 2+ channels in pain transmission, but the role of low voltage-activated, T-type Ca 2+ channels in nociception has not been investigated. The Kim and Chung rodent model of neuropathy [Pain 50 (1992) 355] was used to induce mechanical and cold allodynia in the ipsilateral hindpaw. In vivo electrophysiological techniques were used to record the response of dorsal horn neurones to innocuous and noxious electrical and natural (mechanical and thermal) stimuli after spinal nerve ligation. Spinal ethosuximide (5–1055 μg) exerted dose-related inhibitions of both the electrically and low- and high-intensity mechanical and thermal evoked neuronal responses and its profile remained unaltered after neuropathy. Measures of spinal cord hyperexcitability were most susceptible to ethosuximide. This study, for the first time, indicates a possible role for low voltage-activated Ca 2+ channels in sensory transmission.

Modulation of visceral nociceptive responses of rat spinal dorsal horn neurons by sympathectomy.

We determined whether sympathectomy modulates visceral nociception under physiological or inflammatory conditions. Recordings of sacral spinal dorsal horn neurons with sustained responses were performed in pentobarbitone-anesthetized rats. Graded colorectal distension (CRD, 20-100 mmHg) was used as a visceral nociceptive stimulus. Inflammation was induced by intracolonic instillation of turpentine (25%). Sympathectomy was produced by administering 6-hydroxydopamine. Inflammation produced an increase in the CRD-evoked responses. The CRD-evoked responses were attenuated following sympathectomy both under control and inflammatory conditions. These changes in the CRD-evoked responses were associated with corresponding changes in spontaneous discharge rate. The convergent input evoked by noxious pinch of the skin was not changed by any of the experimental conditions. The results indicate that sympathectomy attenuates visceral nociceptive responses and spontaneous activity of sacral spinal cord neurons, without effect on convergent cutaneous inputs, both under physiological and inflammatory conditions.

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.

Effects of Glutamate Receptor Antagonists on Spinal Dorsal Horn Neurons During Zymosan-Induced Inflammation in Rats

These experiments examined the effects of spinal administration of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV), the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), or the metabotropic glutamate receptor antagonist DL-2-amino-3-phosphonoproprionic acid (AP3) on responses of spinal dorsal horn neurons evoked by thermal and mechanical stimuli applied to the rat hindpaw in either an inflamed or noninflamed state. Administration of APV, DNQX, or AP3 decreased heat-evoked neuronal discharges of wide dynamic range (WDR) neurons that were previously augmented by zymosan-induced inflammation. APV and DNQX also decreased heat-evoked discharges of WDR neurons that were previously unaffected by saline injection. Administration of either APV or DNQX, but not AP3, decreased heat-evoked neuronal discharges of nociceptive-specific (NS) neurons in both zymosan- and saline-injected rats. These data suggest that NMDA and non-NMDA receptors contribute to spinal processing of thermal stimuli in both the inflamed and noninflamed state, whereas metabotropic glutamate receptors might serve a role that is unique to WDR neurons in the inflamed state. Only DNQX consistently increased mechanical response thresholds and decreased slopes of the mechanical stimulus response functions (SRFs) of NS and WDR neurons, but this effect was observed in both inflamed and noninflamed states. These data suggest that spinal processing of mechanical stimuli is preferentially mediated by glutamate acting at non-NMDA receptors in either the inflamed or noninflamed state.

Variable effects of nitrous oxide at multiple levels of the central nervous system in goats.

The direct and indirect effects of nitrous oxide (N2O) on the nociceptive responses of lumbar dorsal horn neurons, and the indirect effects on midbrain reticular formation (MRF) neurons and thalamic neurons were determined in goats anaesthetized with isoflurane. The technique used enabled the differential delivery of N2O to either the torso or the cerebral circulation, thus allowing assessment of the direct spinal and indirect brain effects of N2O. Systemic delivery of N2O appeared to have divergent effects, facilitating (4/11) or depressing (7/11) the responses of dorsal horn neurons. Such divergent effects were also observed when N2O was differentially delivered to the circulation in the torso (i.e. the spinal cord). Likewise, MRF and thalamic responses to noxious stimulation were variably affected by administration of N2O to the torso, with some cells facilitated (7/13 MRF neurons, 3/8 thalamic neurons) and others depressed (6/13 MRF neurons, 5/8 thalamic neurons). It appears that N2O has variable effects on the caprine CNS. The facilitatory action of N2O might partially explain why it is a relatively weak anaesthetic.

Changes in dorsal horn neuronal responses in an experimental wrist contracture model

Joint contracture, a major complication after casting, usually makes the therapeutic outcome worse by causing a limited range of motion and related pain. We developed rat models of wrist contracture with fracture of the radius (group A) and wrist contracture without fracture (group B), and investigated whether contracture and fracture changed the characteristics of cervical dorsal horn neuronal responses and the behavior of the animals. After 4 weeks of immobilization, both groups showed wrist contracture and disuse tendencies in the treated forelimb. In an electrophysiological study, the responses of 403 cervical dorsal horn neurons to mechanical stimuli were examined. In normal (control) animals, the neurons had the following distribution: 63% were low-threshold (LT); 15% were high-threshold (HT); and 22% were wide-dynamic-range (WDR). In group A, the distribution of the neurons changed to 51% LT, 16% HT, and 33% WDR. Similar changes were observed for group B. Responses during wrist movement were also examined. Forty-one percent of cells in the control group were responsive to the movements, whereas the number of neurons responding to motion stimulus in both groups A and B was increased, to 77%. The changed population of WDR and LT neurons responding to wrist movement suggests that the characteristics of dorsal horn neurons may undergo plastic changes after contracture.

Supraspinal vs spinal sites of the antinociceptive action of the subtype-selective NMDA antagonist ifenprodil

The N-methyl-D-aspartate (NMDA) antagonist ifenprodil and several structurally related compounds are highly selective for the NR2B-containing receptor subtype. This selectivity could provide an explanation for the reported difference of the analgesic and side-effect profile of ifenprodil-like compounds from other NMDA antagonists. In this work, we have queried if the ifenprodil-induced antinociception can be attributed to the block of NMDA receptors in the spinal cord. Ifenprodil and some other NMDA antagonists (MK-801, memantine) were tested in a model of inflammatory pain (Randall–Selitto) in rats. The in vivo NMDA antagonism was assessed in anaesthetised rats on responses of spinal dorsal horn (DH) neurones to iontophoretic NMDA and in the model of single motor unit (SMU) wind-up. Ifenprodil, MK-801 and memantine dose-dependently increased nociceptive thresholds in the Randall–Selitto model. Antinociceptive doses of the channel blockers selectively antagonised NMDA responses of DH neurones and inhibited wind-up. In contrast, antinociceptive doses of ifenprodil did not show any NMDA antagonism in electrophysiological tests. Although ifenprodil did not inhibit the SMU responses to noxious stimuli in spinalised rats, it markedly and dose-dependently inhibited nociceptive SMU responses in sham-spinalised rats. These results argue against the spinal cord being the principal site of antinociceptive action of ifenprodil; supraspinal structures seem to be involved in this effect.

An excitatory role for 5-HT in spinal inflammatory nociceptive transmission; state-dependent actions via dorsal horn 5-HT 3 receptors in the anaesthetized rat

The involvement of 5-HT 3 receptor mediated modulation of formalin and carrageenan induced inflammatory transmission was investigated. The effects of the selective 5-HT 3 receptor antagonist ondansetron on the electrically evoked responses of dorsal horn neurones in normal animals were compared to those following carrageenan. The effect of pre-treatment on the formalin response was also studied. Ondansetron had no significant effect on the electrically evoked responses of dorsal horn neurones in normal animals or following carrageenan induced inflammation, but significantly inhibited both phases of the formalin response. Our results suggest that 5-HT 3 receptors in the spinal cord have no significant role under normal conditions. However, during formalin (but not carrageenan) induced inflammation this system is activated, maintaining the response of nociceptive spinal neurones to peripheral formalin.