Responses Of Nociceptive Neurons Research Articles

Dorsal horn antinociception mediated by the paraventricular hypothalamic nucleus and locus coeruleous: A comparative study

The noradrenergic descending projection originating in the locus coeruleous (LC), as well as the oxytocinergic descending projection originating in the paraventricular hypothalamic nucleus (PVN), plays a pivotal role in nociception. The mechanisms used by these two systems to modulate synaptic nociceptive transmission in the dorsal horn have been well studied independently. However, little is known about interactions between them. Here, it is shown that both PVN and LC electric stimulation inhibit A-delta, C-fiber, and postdischarge nociceptive neuronal responses in the same dorsal horn wide dynamic range neurons. Moreover, simultaneous stimulation of both the PVN and LC produces synergic inhibitory effects. In addition, LC electrolytic lesion or intrathecal administration of the alpha-2-adrenoceptor antagonist yohimbine (YOH) blocks the inhibitory effect produced by PVN stimulation in A-delta and the postdischarge, without affecting the inhibition of C-fiber responses. The results suggest that the PVN could inhibit dorsal horn nociceptive responses directly or indirectly by modulating the LC descending noradrenergic system.

Spontaneous firing and evoked responses of spinal nociceptive neurons are attenuated by blockade of P2X3 and P2X2/3 receptors in inflamed rats

P2X3 and P2X2/3 receptors are selectively expressed on primary afferent nociceptors and have been implicated in modulating nociception in different models of pathological pain, including inflammatory pain. In an effort to delineate further the role of P2X3 receptors (homomeric and heteromeric) in the modulation of nociceptive transmission after a chronic inflammation injury, A-317491, a potent and selective P2X3-P2X2/3 antagonist, was administered to CFA-inflamed rats in order to examine its effects on responses of spinal dorsal horn neurons to mechanical and thermal stimulation. Systemic injection of A-317491 (30 μmol/kg, i.v.) reduced the responses of wide-dynamic-range (WDR) and nociceptive specific (NS) neurons to both high-intensity mechanical (pinch) and heat (49°C) stimulation. A-317491 also decreased low-intensity (10 g von Frey hair) mechanically evoked activity of WDR neurons but did not alter WDR neuronal responses to cold stimulation (5°C). Spontaneous firing of WDR neurons in CFA-inflamed rats was also significantly attenuated by A-317491 injection. By using immunohistochemistry, P2X3 receptors were demonstrated to be enhanced in lamina II of the spinal dorsal horn after inflammation. In summary, blockade of P2X3 and P2X2/3 receptors dampens mechanical- and heat-related signaling, as well as nonevoked activity of key classes of spinal nociceptive neurons in inflamed animals. These data suggest that P2X3 and/or P2X2/3 receptors have a broad contribution to somatosensory/nociceptive transmission in rats with a chronic inflammatory injury and are consistent with previous behavioral data demonstrating antiallodynic and antihyperalgesic effects of receptor antagonists.

Is Constant Current or Constant Voltage Spinal Cord Stimulation Superior for the Suppression of Nociceptive Visceral and Somatic Stimuli? A Rat Model

This study compares the effects of constant current (CC) and constant voltage (CV) spinal cord stimulation (SCS) at various frequencies and intensities on standard nociceptive measurements in rats, the visceromotor reflex (VMR) and neuronal activity, during noxious visceral and somatic stimuli. Abdominal muscle electromyographic activity changes were measured to indicate VMR, and extracellular activity of L6-S2 spinal neurons was recorded during somatic (pinching) and noxious visceral stimulation (colorectal distension [CRD], 60 mmHg) in anesthetized rats. A stimulating (unipolar ball) electrode at L2-L3 delivered CC- or CV-SCS at varied frequencies and intensities. CC-SCS reduced VMR evoked by CRD significantly more than CV-SCS (p < 0.05). For neuronal activity, high-frequency CC-SCS (40 and 100 Hz) and CV-SCS (100 Hz) effectively reduced intraspinal somatic nociceptive transmission more than low-frequency SCS (2 Hz). No significant differences were observed between the effects of CC- and CV-SCS on spontaneous activity and nociceptive responses of spinal neurons to noxious CRD following short- (five to ten minutes) or long-term (20-30 min) SCS. Although high-frequency CC- and CV-SCS may be more useful for the management of somatic pain, CC-SCS may be more effective for treating complex pain systems like visceral hypersensitivity.

Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

BackgroundWe previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC). The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA) to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS) delivered to the BLA on nociceptive responses in the rat PFC.ResultsHFS induced long lasting suppression (LLS) of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA) receptor antagonists (2-amino-5-phosphonovaleric acid (APV), dizocilpine (MK-801)) and also metabotropic glutamate receptor (mGluR) group antagonists (α-methyl-4-carboxyphenylglycine (MCPG), and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495)), prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA) on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA) injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride) and D4 (3-{[4-(4-chlorophenyl) piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870)), microinjected into the PFC, inhibited LLS of nociceptive responses.ConclusionsOur results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

MicroRNA-143 expression in dorsal root ganglion neurons

The unpleasant sensory and emotional experience of pain is initiated by excitation of primary afferent nociceptive neurons. Nerve damage or inflammation induces changes in nociceptive DRG neurons which contribute to both peripheral and central sensitization of pain-sensitive pathways. Recently, blockade of microRNA synthesis has been found to modulate the response of nociceptive neurons to inflammatory stimuli. However, little is known about the contributions of individual miRNAs to painful conditions. We compared miRNA expression in mouse sensory neurons and focussed on the localisation and control of miR-143. Using miRNA-arrays we compared the microRNA expression profile of intact lumbar DRG with one-day-old DRG cultures and found that nine miRNAs including miR-143 showed lower expression levels in cultures. Subsequent RT-qPCR confirmed array data and in-situ hybridisation localised miR-143 in the cytosol of sensory DRG neurons in situ and in vitro. Analysis of microbead-enriched neuron cultures showed significantly higher expression levels of miR-143 in isolectin B4 (I-B4) binding sensory neurons compared with neurons in the I-B4 negative flow-through fraction. In animal models of peripheral inflammation (injection of Complete Freund's Adjuvant, CFA) and nerve damage (transection of the sciatic nerve), we found that expression levels of miR-143 were significantly lower in DRGs ipsilateral to CFA injection or after nerve damage. Taken together, our data demonstrate for the first time miR-143 expression in nociceptive neurons. Since expression levels of miR-143 were higher in I-B4 positive neurons and declined in response to inflammation but not axotomy, miR-143 could selectively contribute to mRNA regulation in specific populations of nociceptors.

Inhibition of nociceptive responses after systemic administration of amidated kyotorphin.

BACKGROUND AND PURPOSEKyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood–brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide – KTP-NH2).EXPERIMENTAL APPROACHWe synthesized KTP-NH2. This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH2. Binding to opioid receptors and toxicity were also measured.KEY RESULTSKTP-NH2, unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH2 inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone.CONCLUSIONS AND IMPLICATIONSAmidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH2 may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications.

P.2.017 Antinociceptive effects of intrathecally administered nociceptin/orphanin FQ receptor agonists in the rat tail flick test

High density Nociceptin/Orphanin FQ (N/OFQ) and its receptor (NOPr) have been found in the ventrolateral periaqueductal gray (vlPAG), a main output pathway involved in the descending pain-control system. Our previous study demonstrated that the microinjection of N/OFQ into the vlPAG markedly facilitated nociceptive responses of spinal dorsal horn neurons. The aim of the present work was to further provide evidence for the supraspinal mechanisms of action for N/OFQ-mediated nociceptive facilitation by examining the effect of N/OFQ in the vlPAG on neurotransmitter release in the descending pain-control system, including the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis (NGC) and dorsal horn of the spinal cord. The results showed that the microinjection of N/OFQ into the vlPAG produced robust decreases in 5-hydroxytryptamine (5-HT, serotonin), norepinephrine (NE), and γ-aminobutyric acid (GABA), and increase in glutamate (Glu) release in the spinal dorsal horn. Spinal application of 5-HT, 2-Me-5-HT (5-HT3 receptor agonist), muscimol (GABAA receptor agonist), and baclofen (GABAB receptor agonist) significantly blocked intra-vlPAG-induced facilitation on nociceptive responses. However, the extracellular concentrations of these neurotransmitters in the NRM and NGC exhibited diversity following intra-vlPAG of N/OFQ. In the NRM, intra-vlPAG injection of N/OFQ significantly decreased 5-HT, NE, and Glu, but increased GABA release. Differently, in the NGC, both NE and GABA releases were attenuated by intra-vlPAG of N/OFQ, whereas the concentration of 5-HT and Glu exhibited a trend to increase. These findings provide direct support for the hypothesis that intra-PAG of N/OFQ-induced facilitation of nociceptive responses is associated with the release of 5-HT, NE, and amino acids.

Hippocampal CA1/subiculum-prefrontal cortical pathways induce plastic changes of nociceptive responses in cingulate and prelimbic areas

BackgroundProjections from hippocampal CA1-subiculum (CA1/SB) areas to the prefrontal cortex (PFC), which are involved in memory and learning processes, produce long term synaptic plasticity in PFC neurons. We examined modifying effects of these projections on nociceptive responses recorded in the prelimbic and cingulate areas of the PFC.ResultsExtracellular unit discharges evoked by mechanical noxious stimulation delivered to the rat-tail and field potentials evoked by a single stimulus pulse delivered to CA1/SB were recorded in the PFC. High frequency stimulation (HFS, 100 Hz) delivered to CA1/SB, which produced long-term potentiation (LTP) of field potentials, induced long-term enhancement (LTE) of nociceptive responses in 78% of cases, while, conversely, in 22% responses decreased (long-term depression, LTD). These neurons were scattered throughout the cingulate and prelimbic areas. The results obtained for field potentials and nociceptive discharges suggest that CA1/SB-PFC pathways can produce heterosynaptic potentiation in PFC neurons. HFS had no effects on Fos expression in the cingulated cortex. Low frequency stimulation (LFS, 1 Hz, 600 bursts) delivered to the CA1/SB induced LTD of nociceptive discharges in all cases. After recovery from LTD, HFS delivered to CA1/SB had the opposite effect, inducing LTE of nociceptive responses in the same neuron. The bidirectional type of plasticity was evident in these nociceptive responses, as in the homosynaptic plasticity reported previously. Neurons inducing LTD are found mainly in the prelimbic area, in which Fos expression was also shown to be inhibited by LFS. The electrophysiological results closely paralleled those of immunostaining. Our results indicate that CA1/SB-PFC pathways inhibit excitatory pyramidal cell activities in prelimbic areas.ConclusionPressure stimulation (300 g) applied to the rat-tail induced nociceptive responses in the cingulate and prelimbic areas of the PFC, which receives direct pathways from CA1/SB. HFS and LFS delivered to the CA1/SB induced long-term plasticity of nociceptive responses. Thus, CA1/SB-PFC projections modulate the nociceptive responses of PFC neurons.

Oxytocin, but not vassopressin, modulates nociceptive responses in dorsal horn neurons

Oxytocin (OT) and vasopressin (VP) are synthesized and secreted by the paraventricular hypothalamic nucleus (PVN), and both peptides have been implicated in the pain modulatory system. In the spinal cord, activation of OT-containing axons modulates nociceptive neuronal responses in dorsal horn neurons; however, it is not known whether the direct VPergic descending projection participates. Here, we show that both PVN electrical stimulation and topical application of OT in the vicinity of identified and recorded dorsal horn WDR selectively inhibit Adelta and C-fiber responses. In contrast, the topical administration of VP on the same neurons did not affect the nociceptive responses. In addition, the reduction in nociceptive responses caused by PVN stimulation or OT administration was blocked with a selective OT antagonist. The results suggest that the VP descending projection does not modulate the antinociceptive effects mediated by the PVN on dorsal horn neurons; instead, it is the hypothalamic-spinal OT projection that regulates nociceptive information.

Nociceptive Processing by Anterior Cingulate Pyramidal Neurons

Although the cingulate cortex is frequently activated in acute human pain studies, postsynaptic responses are not known nor are links between nociceptive afferents, neuronal responses, and outputs to other structures. Intracellular potentials were recorded from neurobiotin-injected, pyramidal neurons in anterior cingulate area 24b following noxious stimulation of the sciatic nerve in anesthetized rabbits. Layer IIIc pyramids had extensive and horizontally oriented basal dendrites in layer IIIc where nociceptive afferents terminate. They had the longest excitatory postsynaptic potentials (EPSPs; 545 ms) that were modulated with hyperpolarizing currents. Pyramids in layer V had an intermediate tuft of oblique apical dendrites in layer IIIc that were 150-350 microm from somata in layer Va and 351-550 microm in layer Vb. Although average EPSP durations were short in layers II-IIIab (222 +/- 31), Va (267 +/- 65), and Vb (159 +/- 31), there were five neurons in layers IIIab-Va that had EPSP durations lasting >300 ms (548 +/- 63 ms). Neurons in layers IIIc, Va, and Vb had the highest amplitude EPSPs (6.25, 6.84 +/- 0.58, and 6.4 +/- 0.47 mV, respectively), whereas those in layers II-IIIab were 5 +/- 0.56 mV. Nociceptive responses in layer Vb were complex and some had initial inhibitory postsynaptic potentials with shorter-duration EPSPs. Layers II-IIIab had dye-coupled pyramids and EPSPs in these layers had short durations (167 +/- 33 ms) compared with those in layers IIIc-Va (487 +/- 28 ms). In conclusion there are two populations of anterior cingulate cortex pyramids with EPSPs of significantly different durations, although their dendritic morphologies do not predict EPSP duration. Short-duration EPSPs are thalamic-mediated, nociceptive responses lasting < or =200 ms. Longer, "integrative" EPSPs are >350 ms and are likely modulated by intracortical axon collateral discharges. These findings suggest that links between nociception and projections to cortical and motor systems are instantaneous because nociceptive responses are generated directly by pyramidal projection neurons in all layers.

Brainstem Regions Affecting Minimum Alveolar Concentration and Movement Pattern during Isoflurane Anesthesia

Spinal transection or selective delivery of volatile anesthetics to the spinal cord reduces minimum alveolar concentration (MAC), whereas precollicular decerebration does not. The authors sought to determine which brainstem regions influence anesthetic requirements and movement responses with isoflurane. Movement (biceps femoris electromyogram) and MAC were measured in adult rats before and after decerebration at the precollicular, mid-collicular, pontine or medullary level, or decerebellation. Additional experiments assessed the effects of lidocaine inactivation of the mesencephalic locomotor region on MAC and the effects of isoflurane on nociceptive neuronal responses in this region. Transections placed at the level of the mid-colliculus, rostral pons, and pontomedullary junction significantly reduced MAC by approximately 10, 40, and 45%, respectively. MAC was decreased 9% after mid-medullary transections that were placed caudal to the nucleus raphe magnus but rostral to the dorsal reticular nucleus; however, only weak, single movements occurred. Caudal medullary transections at the obex decreased MAC by 60%. Bilateral inactivation of the mesencephalic locomotor region with lidocaine caused a reversible, 32% decrease in MAC and reduced the number and amplitude of movements at sub-MAC isoflurane concentrations. Neuronal responses of mesencephalic locomotor region neurons to supramaximal noxious tail clamp were reduced by 87% by 1.2 MAC isoflurane. The authors conclude that the mesencephalic locomotor region influences anesthetic requirements and promotes repetitive movement with sub-MAC isoflurane by facilitating ventral spinal locomotor circuits, where anesthetics seem to exert their key immobilizing effects. However, net brainstem influences on MAC seem to result from interaction among descending nociceptive and locomotor modulatory pathways.

Plasticity changes of neuronal activities in central lateral nucleus by stimulation of the anterior cingulate cortex in rat

The medial thalamus (MT) and anterior cingulate cortex (ACC) are essential components in mediating the affective emotional-aspect of pain. Whether ACC modulates the neuron activity in MT has not been elucidated and clarifying this point will further reveal the neurobiological mechanism underlying pain related emotions. In the present study, we used in vivo single unit recording and retrograde tracing technique to demonstrate that the majority of examined neurons in the central lateral nucleus (CL), an important nucleus of MT, responded to noxious stimulation. Tetanic stimulation in the ACC increased spike activities of nociceptive-responding neurons in the CL; retrograde tracing by fluorogold in the CL showed the positive neurons are distributed bilaterally in the ACC. Taken together, we demonstrated descending modulation to nociceptive responses of CL neurons by direct projections from the ACC, which may underlie the neuronal mechanism of negative pain emotions.

Nociceptin/Orphanin FQ in PAG modulates the release of amino acids, serotonin and norepinephrine in the rostral ventromedial medulla and spinal cord in rats

High density Nociceptin/Orphanin FQ (N/OFQ) and its receptor (NOPr) have been found in the ventrolateral periaqueductal gray (vlPAG), a main output pathway involved in the descending pain-control system. Our previous study demonstrated that the microinjection of N/OFQ into the vlPAG markedly facilitated nociceptive responses of spinal dorsal horn neurons. The aim of the present work was to further provide evidence for the supraspinal mechanisms of action for N/OFQ-mediated nociceptive facilitation by examining the effect of N/OFQ in the vlPAG on neurotransmitter release in the descending pain-control system, including the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis (NGC) and dorsal horn of the spinal cord. The results showed that the microinjection of N/OFQ into the vlPAG produced robust decreases in 5-hydroxytryptamine (5-HT, serotonin), norepinephrine (NE), and γ-aminobutyric acid (GABA), and increase in glutamate (Glu) release in the spinal dorsal horn. Spinal application of 5-HT, 2-Me-5-HT (5-HT3 receptor agonist), muscimol (GABAA receptor agonist), and baclofen (GABAB receptor agonist) significantly blocked intra-vlPAG-induced facilitation on nociceptive responses. However, the extracellular concentrations of these neurotransmitters in the NRM and NGC exhibited diversity following intra-vlPAG of N/OFQ. In the NRM, intra-vlPAG injection of N/OFQ significantly decreased 5-HT, NE, and Glu, but increased GABA release. Differently, in the NGC, both NE and GABA releases were attenuated by intra-vlPAG of N/OFQ, whereas the concentration of 5-HT and Glu exhibited a trend to increase. These findings provide direct support for the hypothesis that intra-PAG of N/OFQ-induced facilitation of nociceptive responses is associated with the release of 5-HT, NE, and amino acids.

Astroglia in Medullary Dorsal Horn (Trigeminal Spinal Subnucleus Caudalis) Are Involved in Trigeminal Neuropathic Pain Mechanisms

The aim of this study was to investigate whether astroglia in the medullary dorsal horn (trigeminal spinal subnucleus caudalis; Vc) may be involved in orofacial neuropathic pain following trigeminal nerve injury. The effects of intrathecal administration of the astroglial aconitase inhibitor sodium fluoroacetate (FA) were tested on Vc astroglial hyperactivity [as revealed by glial fibrillary acid protein (GFAP) labeling], nocifensive behavior, Vc extracellular signal-regulated kinase phosphorylation (pERK), and Vc neuronal activity in inferior alveolar nerve-transected (IANX) rats. Compared with sham-control rats, a significant increase occurred in GFAP-positive cells in ipsilateral Vc at postoperative day 7 in IANX rats, which was prevented following FA administration. FA significantly increased the reduced head withdrawal latency to high-intensity heat stimulation of the maxillary whisker pad skin in IANX rats, although it did not significantly affect the reduced escape threshold to low-intensity mechanical stimulation of the whisker skin in IANX rats. FA also significantly reduced the increased number of pERK-like immunoreactive cells in Vc and the enhanced Vc nociceptive neuronal responses following high-intensity skin stimulation that were documented in IANX rats, and glutamine administration restored the enhanced responses. These various findings provide the first documentation that astroglia is involved in the enhanced nociceptive responses of functionally identified Vc nociceptive neurons and in the associated orofacial hyperalgesia following trigeminal nerve injury.

Paraventricular oxytocinergic hypothalamic prevention or interruption of long-term potentiation in dorsal horn nociceptive neurons: Electrophysiological and behavioral evidence

Spinal long-term potentiation (LTP) elicited by noxious stimulation enhances the responsiveness of dorsal horn nociceptive neurons to their normal input, and may represent a key mechanism of central sensitization by which acute pain could turn into a chronic pain state. This study investigated the electrophysiological and behavioral consequences of the interactions between LTP and descending oxytocinergic antinociceptive mechanisms mediated by the hypothalamic paraventricular nucleus (PVN). PVN stimulation or intrathecal oxytocin (OT) reduced or prevented the ability of spinal LTP to facilitate selectively nociceptive-evoked responses of spinal wide dynamic range (WDR) neurons recorded in anesthetized rats. In a behavioral model developed to study the effects of spinal LTP on mechanical withdrawal thresholds in freely moving rats, the long-lasting LTP-mediated mechanical hyperalgesia was transiently interrupted or prevented by either PVN stimulation or intrathecal OT. LTP mediates long-lasting pain hypersensitivity that is strongly modulated by endogenous hypothalamic oxytocinergic descending controls.

Propofol Produces Immobility via Action in the Ventral Horn of the Spinal Cord by a GABAergic Mechanism

We investigated the actions of propofol and isoflurane on nociceptive responses of neurons in the spinal cord. We determined nociceptive responses of lumbar neurons in the dorsal horn (<1200 microm) and ventral horn (>1200 microm) of decerebrate rats before and during propofol (1 effective dose, ED(50)) or isoflurane (1 minimum alveolar concentration) anesthesia. During recording of ventral horn neurons, we administered picrotoxin by infusion to determine whether isoflurane and propofol differed in their effects at the gamma aminobutyric acid (GABA) Type A receptors. We also determined whether decerebration altered propofol requirements to produce immobility. Decerebration did not affect propofol requirements. The ED(50) for propofol was 497 +/- 58 microg x kg(-1) x min(-1) in intact rats and 420 +/- 65 microg x kg(-1) x min(-1) in decerebrated rats (P > 0.05), with corresponding propofol blood concentrations of 8.1 +/- 1.1 microg/mL and 7.3 +/- 1.1 microg/mL, respectively (P > 0.05). Propofol did not significantly depress dorsal horn neurons, but isoflurane depressed the responses to 56% of control (P < 0.05). Propofol depressed ventral horn neurons to 47% of control, whereas isoflurane depressed ventral horn neurons to 20% of control. Picrotoxin significantly reversed the depressant effect of propofol on ventral horn neuronal responses (79% of control, not significantly different from control). Pic- rotoxin, however, had no effect on isoflurane's depression of ventral horn neuronal responses (26% of control). Propofol acts in the spinal cord to produce immobility. This depressive effect occurs in the ventral horn and is mediated mainly by GABA(A) receptors. Isoflurane also depresses neurons in the ventral horn; however, isoflurane actions at the GABA(A) receptor are either weak or overridden by other effects in the ventral horn.

Volatile Anesthetic Effects on Midbrain-elicited Locomotion Suggest that the Locomotor Network in the Ventral Spinal Cord Is the Primary Site for Immobility

Volatile anesthetics produce immobility primarily by action in the spinal cord; however, anesthetic effects among different neuronal classes located in different spinal regions, and how they relate to immobility, are not understood. In decerebrated rats, effects of isoflurane and halothane on movement elicited by electrical microstimulation of the mesencephalic locomotor region (MLR) were assessed in relation to minimum alveolar concentration (MAC). Anesthetic effects on step frequency and isometric limb force were measured. The authors also examined effects of MLR stimulation on responses of nociceptive dorsal horn neurons and limb force responses to tail clamp. Mean isoflurane requirements to block MLR-elicited stepping were slightly but significantly greater than MAC by 10%. Mean halothane requirements to block MLR-elicited stepping were greater than those for isoflurane and exceeded MAC by 20%. From 0.4 to 1.3 MAC (but not 0.0 to 0.4 MAC), there was a dose-dependent reduction in the frequency and force of hind limb movements elicited by MLR stimulation during both anesthetics. MLR stimulation inhibited noxious stimulus evoked responses of dorsal horn neurons by approximately 80%. Aptly, MLR stimulation produced analgesia that outlasted the midbrain stimulus by at least 15 s, as indicated by an 81% reduction in hind limb force elicited noxious tail clamp. Because electrical stimulation of the MLR elicits movement independent of dorsal horn activation, the immobilizing properties of isoflurane and halothane are largely independent of action in the dorsal horn. The results suggest that volatile anesthetics produce immobility mainly by action on ventral spinal locomotor networks.

Critical Role of the Rostral Ventromedial Medulla in Early Spinal Events Leading to Chronic Constriction Injury Neuropathy in Rats

Neuropathic pain is a major clinical problem, and several animal models have been developed to investigate its mechanisms and its treatment. In this report, the role of the rostral ventromedial medulla (RVM) in the early events of the chronic constriction injury (CCI) model was investigated in behavioral and electrophysiological experiments. Placing the 4 CCI ligatures around the sciatic nerve induced large discharges and residual ongoing activity in spinal nociceptive neurons. Two weeks after CCI ligation, the rats showed behavioral hyperalgesia and allodynia as well as increased ongoing activity and responsiveness of spinal nociceptive neurons to innocuous and noxious stimuli. Blockade of excitatory synapses in the RVM by a kynurenate microinjection (2 nmol in 0.5 muL) 5 minutes before placement of the sciatic ligatures had no immediate effect on spinal neuronal activity but largely prevented the activation of spinal neurons. In kynurenate microinjected rats, behavioral hyperalgesia and allodynia developed slowly and incompletely, which corresponded with an incompletely developed hyperexcitability of spinal neurons. To the best of our knowledge, these results show for the first time that the initial response to nerve damage requires facilitation from the RVM. The present and previous findings indicate that descending facilitation from brainstem nuclei critically contributes to the spinal hyperexcitability that underlies neuropathic pain. The present results indicate that this contribution begins at the very moment the nerve is damaged and should be prevented and treated accordingly.

Inhibitory effects of amygdala stimulation on the responses of nociceptive neurons in the rat medullary dorsal horn to peripheral natural stimulation

Inhibitory effects of amygdala stimulation on the responses of nociceptive neurons in the rat medullary dorsal horn to peripheral natural stimulation

Peripheral inflammation undermines the plasticity of the isolated spinal cord.

Peripheral capsaicin treatment induces molecular changes that sensitize the responses of nociceptive neurons in the spinal dorsal horn. The current studies demonstrate that capsaicin also undermines the adaptive plasticity of the spinal cord, rendering the system incapable of learning a simple instrumental task. In these studies, male rats are transected at the second thoracic vertebra and are tested 24 to 48 hours later. During testing, subjects receive shock to one hindleg when it is extended (controllable stimulation). Rats quickly learn to maintain the leg in a flexed position. Rats that have been injected with capsaicin (1% or 3%) in the hindpaw fail to learn, even when tested on the leg contralateral to the injection. This learning deficit lasts at least 24 hours. Interestingly, training with controllable electrical stimulation prior to capsaicin administration protects the spinal cord against the maladaptive effects. Rats pretrained with controllable stimulation do not display a learning deficit or tactile allodynia. Moreover, controllable stimulation, combined with naltrexone, reverses the capsaicin-induced deficit. These data suggest that peripheral inflammation, accompanying spinal cord injuries, might have an adverse effect on recovery.