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Pain modulates rhythmic neuronal activity recorded by Electroencephalography (EEG) in humans. Our laboratory previously showed that rat models of acute and neuropathic pain manifest increased power in primary somatosensory cortex (S1) recorded by electrocorticography (ECoG). In this study, we hypothesized that pain increases EEG power and corticocortical coherence in different rat models of pain, whereas treatments with clinically effective analgesics reverse these changes. Our results show increased cortical power over S1 and prefrontal cortex (PFC) in awake, freely behaving rat models of acute, inflammatory and neuropathic pain. Coherence between PFC and S1 is increased at a late, but not early, time point during the development of neuropathic pain. Electroencephalography power is not affected by ibuprofen in the acute pain model. However, pregabalin and mexiletine reverse the changes in power and S1-PFC coherence in the inflammatory and neuropathic pain models. These data suggest that quantitative EEG might be a valuable predictor of pain and analgesia in rodents.

Oscillations are fundamental to communication between neuronal ensembles. We previously reported that pain in awake rats enhances synchrony in primary somatosensory cortex (S1) and attenuates coherence between S1 and ventral posterolateral (VPL) thalamus. Here, we asked whether similar changes occur in anesthetized rats and whether pain modulates phase-amplitude coupling between VPL and S1. We also hypothesized that the suppression of burst firing in VPL using Z944, a novel T-type calcium channel blocker, restores S1 synchrony and thalamocortical connectivity. Local field potentials were recorded from S1 and VPL in anesthetized rats 7 days after sciatic chronic constriction injury (CCI). In rats with CCI, low-frequency (4-12 Hz) synchrony in S1 was enhanced, whereas VPL-S1 coherence and theta-gamma phase-amplitude coupling were attenuated. Moreover, Granger causality showed decreased informational flow from VPL to S1. Systemic or intrathalamic delivery of Z944 to rats with CCI normalized these changes. Systemic Z944 also reversed thermal hyperalgesia and conditioned place preference. These data suggest that pain-induced cortical synchrony and thalamocortical disconnectivity are directly related to burst firing in VPL.

Neuronal ensemble activity entrained by local field potential (LFP) patterns underlies a variety of brain functions, including emotion, cognition, and pain perception. Recent advances in machine learning approaches may enable more effective methods for analyzing LFP patterns across multiple brain areas than conventional time-frequency analysis. In this study, we tested the performance of two machine learning algorithms, AlexNet and the Transformer models, to classify LFP patterns in eight pain-related brain regions before and during acetic acid-induced visceral pain behaviors. Over short time windows lasting several seconds, applying AlexNet to LFP power datasets, but not to raw time-series LFP traces from multiple brain areas, successfully achieved superior classification performance compared with simple LFP power analysis. Furthermore, applying the Transformer directly to the raw LFP traces achieved significantly superior classification performance than AlexNet when using LFP power datasets. These results demonstrate the utility of the Transformer in the analysis of neurophysiological signals, and pave the way for its future applications in the decoding of more complex neuronal activity patterns. [ABSTRACT FROM AUTHOR]

Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pretreatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray. Specific reactivation of capsaicin-activated vlPAGGABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAGGABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine (DA) release and activation of DA D1-like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception, and it is important to provide new insights for guiding the management of the anesthesia recovery period. [ABSTRACT FROM AUTHOR]

Abstract: Preventive treatment is crucial for patients with chronic migraine (CM). This study explored the association between resting-state cortical oscillations and 3-month treatment outcome in patients with CM. Treatment-naïve patients with CM were recruited with their demographic data, psychosocial data, and headache profiles as well as the healthy controls (HCs). Resting-state cortical activities were recorded using an electroencephalogram and analysed using source-based and electrode-based spectral power method. The regions of interest were the bilateral primary somatosensory (S1) and visual (V1) cortices. After 3-month treatment with flunarizine, patients with CM were categorized into responders and nonresponders. Demographic, clinical, and electroencephalogram data from 72 patients with CM and 50 HCs were analysed. Elevated anxiety, depression, and stress were observed in patients with CM. Theta power in bilateral S1 and alpha and gamma powers in the right S1 increased in patients with CM. Nonresponders (n = 34) exhibited larger alpha powers in bilateral V1 than those in responders (n = 38). Alpha powers also exhibited significant correlations with changes of monthly headache days. Notably, in responders and nonresponders, occipital alpha powers did not differ at baseline and in the third month. In conclusion, patients with CM who were not responsive to preventive treatment were associated with augmented resting-state occipital alpha activity. Moreover, changes in migraine attack frequency were associated with baseline occipital alpha power. However, the prognostic feature of visual alpha oscillation seems to be inherent because it is not altered by flunarizine treatment. These findings may be useful for developing personalised migraine treatment plans., (Copyright © 2021 International Association for the Study of Pain.)

The thalamocortical (TC) circuit is closely associated with pain processing. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is predominantly expressed in the ventral posterolateral thalamus (VPL) that has been shown to mediate neuropathic pain. However, the role of VPL HCN2 in modulating TC circuit activity is largely unknown. Here, by using optogenetics, neuronal tracing, electrophysiological recordings, and virus knockdown strategies, we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex (S1HL) as well as mechanical hypersensitivity following spared nerve injury (SNI)-induced neuropathic pain in mice. Either pharmacological blockade or virus knockdown of HCN2 (shRNA-Hcn2) in the VPL was sufficient to alleviate SNI-induced hyperalgesia. Moreover, shRNA-Hcn2 decreased the excitability of TC neurons and synaptic transmission of the VPL–S1HL circuit. Together, our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain. [ABSTRACT FROM AUTHOR]

To identify and validate the neural signatures of resting-state oscillatory connectivity for chronic migraine (CM), we used machine learning techniques to classify patients with CM from healthy controls (HC) and patients with other pain disorders. The cross-sectional study obtained resting-state magnetoencephalographic data from 240 participants (70 HC, 100 CM, 35 episodic migraine [EM], and 35 fibromyalgia [FM]). Source-based oscillatory connectivity of relevant cortical regions was calculated to determine intrinsic connectivity at 1–40 Hz. A classification model that employed a support vector machine was developed using the magnetoencephalographic data to assess the reliability and generalizability of CM identification. In the findings, the discriminative features that differentiate CM from HC were principally observed from the functional interactions between salience, sensorimotor, and part of the default mode networks. The classification model with these features exhibited excellent performance in distinguishing patients with CM from HC (accuracy ≥ 86.8%, area under the curve (AUC) ≥ 0.9) and from those with EM (accuracy: 94.5%, AUC: 0.96). The model also achieved high performance (accuracy: 89.1%, AUC: 0.91) in classifying CM from other pain disorders (FM in this study). These resting-state magnetoencephalographic electrophysiological features yield oscillatory connectivity to identify patients with CM from those with a different type of migraine and pain disorder, with adequate reliability and generalizability. [ABSTRACT FROM AUTHOR]

Chronic pain is a severely debilitating condition that reflects a long-term sensitization of signal transduction in the afferent pain pathway. Among the key players in this pathway are T-type calcium channels, in particular the Cav3.2 isoform. Because of their biophysical characteristics, these channels are ideally suited towards regulating neuronal excitability. Recent evidence suggests that T-type channels contribute to excitability of neurons all along the ascending and descending pain pathways, within primary afferent neurons, spinal dorsal horn neurons, and within pain-processing neurons in the midbrain and cortex. Here we review the contribution of T-type channels to neuronal excitability and function in each of these neuronal populations and how they are dysregulated in chronic pain conditions. Finally, we discuss their molecular pharmacology and the potential role of these channels as therapeutic targets for chronic pain. [ABSTRACT FROM AUTHOR]

Key points: Cortical activity underlying movement‐evoked pain is not well understood, despite being a key symptom of chronic musculoskeletal pain.We combined high‐density electroencephalography with a full‐body reaching protocol in a virtual reality environment to assess cortical activity during movement‐evoked pain in chronic low back pain.Movement‐evoked pain in individuals with chronic low back pain was associated with longer reaction times, delayed peak velocity and greater movement variability.Movement‐evoked pain was associated with attenuated disinhibition in prefrontal motor areas, as evidenced by an attenuated reduction in beta power in the premotor cortex and supplementary motor area. Although experimental pain alters neural activity in the cortex, evidence of changes in neural activity in individuals with chronic low back pain (cLBP) remains scarce and results are inconsistent. One of the challenges in studying cLBP is that the clinical pain fluctuates over time and often changes during movement. The goal of the present study was to address this challenge by recording high‐density electroencephalography (HD‐EEG) data during a full‐body reaching task to understand neural activity during movement‐evoked pain. HD‐EEG data were analysed using independent component analyses, source localization and measure projection analyses to compare neural oscillations between individuals with cLBP who experienced movement‐evoked pain and pain‐free controls. We report two novel findings. First, movement‐evoked pain in individuals with cLBP was associated with longer reaction times, delayed peak velocity and greater movement variability. Second, movement‐evoked pain was associated with an attenuated reduction in beta power in the premotor cortex and supplementary motor area. Our observations move the field forward by revealing attenuated disinhibition in prefrontal motor areas during movement‐evoked pain in cLBP. Key points: Cortical activity underlying movement‐evoked pain is not well understood, despite being a key symptom of chronic musculoskeletal pain.We combined high‐density electroencephalography with a full‐body reaching protocol in a virtual reality environment to assess cortical activity during movement‐evoked pain in chronic low back pain.Movement‐evoked pain in individuals with chronic low back pain was associated with longer reaction times, delayed peak velocity and greater movement variability.Movement‐evoked pain was associated with attenuated disinhibition in prefrontal motor areas, as evidenced by an attenuated reduction in beta power in the premotor cortex and supplementary motor area. [ABSTRACT FROM AUTHOR]

Chronic pain pathologies, which are due to maladaptive changes in the peripheral and/or central nervous systems, are debilitating diseases that affect 20% of the European adult population. A better understanding of the mechanisms underlying this pathogenesis would facilitate the identification of novel therapeutic targets. Functional connectivity (FC) extracted from coherent low-frequency hemodynamic fluctuations among cerebral networks has recently brought light on a powerful approach to study large scale brain networks and their disruptions in neurological/psychiatric disorders. Analysis of FC is classically performed on averaged signals over time, but recently, the analysis of the dynamics of FC has also provided new promising information. Keeping in mind the limitations of animal models of persistent pain but also the powerful tool they represent to improve our understanding of the neurobiological basis of chronic pain pathogenicity, this study aimed at defining the alterations in functional connectivity, in a clinically relevant animal model of sustained inflammatory pain (Adjuvant-induced Arthritis) in rats by using functional ultrasound imaging, a neuroimaging technique with a unique spatiotemporal resolution (100 μm and 2 ms) and sensitivity. Our results show profound alterations of FC in arthritic animals, such as a subpart of the somatomotor (SM) network, occurring several weeks after the beginning of the disease. Also, we demonstrate for the first time that dynamic functional connectivity assessed by ultrasound can provide quantitative and robust information on the dynamic pattern that we define as brain states. While the main state consists of an overall synchrony of hemodynamic fluctuations in the SM network, arthritic animal spend statistically more time in two other states, where the fluctuations of the primary sensory cortex of the inflamed hind paws show asynchrony with the rest of the SM network. Finally, correlating FC changes with pain behavior in individual animals suggest links between FC alterations and either the cognitive or the emotional aspects of pain. Our study introduces fUS as a new translational tool for the enhanced understanding of the dynamic pain connectome and brain plasticity in a major preclinical model of chronic pain. [ABSTRACT FROM AUTHOR]

Background: Clinical and animal studies have found that anxiety and depression are significantly more common after acute myocardial infarction (AMI). The medial prefrontal cortex (PFC) has a dual role: in higher brain functions and in cardiovascular control, making it a logical candidate for explaining the perceived bidirectional heart-brain connection. We used parallel Electrocardiography (ECG) and Electrocorticography (ECoG) registration to investigate AMI-induced changes in medial PFC bioelectrical activity in a rat model of AMI. Materials and methods: Adult male Wistar albino rats were used in the study. Gold-plated recording electrodes were implanted over the frontal cortex for ECoG recording. ECG was recorded via two holter electrodes attached on the skin of the back fixed in place by a jacket. Induction of AMI was performed by isoprenaline (150 mg/kg, i.p.). ECoG and ECG signals were registered at baseline, during 3 hours after isoprenaline administration and at 24 hours after isoprenaline administration. Results: Significant increases of theta, alpha, and beta electroencephalographic (EEG) band power were observed in different time intervals after isoprenaline administration. Significant increase of theta band peak frequency was also observed during the first hour after isoprenaline administration. No statistically significant differences in band-power activity were found between the pre-isoprenaline measurements and 24 hours after administration. Conclusion: Our results demonstrate significant increases in EEG band power of alpha beta and theta bands during isoprenaline-induced AMI model. These are the first findings to connect heart damage during isoprenaline- induced AMI to disturbances in the cortical bioelectrical activity. [ABSTRACT FROM AUTHOR]

Cav 3.2 T-type calcium channels are important regulators of pain signals in the afferent pain pathway, and their activities are dysregulated during various chronic pain states. Therefore, it is reasonable to predict that inhibiting T-type calcium channels in dorsal root ganglion neurons and in the spinal dorsal horn can be targeted for pain relief. This is supported by early pharmacological studies with T-type channel blockers, such as ethosuximide, and by analgesic effects of siRNA depletion of Cav 3.2 channels. In the past 5 years, considerable effort has been applied towards identifying novel classes of T-type calcium channel blockers. Here, we review recent developments in the discovery of novel classes of T-type calcium channel blockers, and their analgesic effects in animal models of pain and in clinical trials.Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. [ABSTRACT FROM AUTHOR]

Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Cav 2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Cav 2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators.Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. [ABSTRACT FROM AUTHOR]

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a "WDR phenotype." After neuropathy was induced, the proportion of coldsensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity. [ABSTRACT FROM AUTHOR]

Enhancing the efficacy of spinal cord stimulation (SCS) is needed to alleviate the burden of chronic pain and dependence on opioids. Present SCS therapies are characterized by the delivery of constant stimulation in the form of trains of tonic pulses (TPs). We tested the hypothesis that modulated SCS using novel time-dynamic pulses (TDPs) leads to improved analgesia and compared the effects of SCS using conventional TPs and a collection of TDPs in a rat model of neuropathic pain according to a longitudinal, double-blind, and crossover design. We tested the effects of the following SCS patterns on paw withdrawal threshold and resting state EEG theta power as a biomarker of spontaneous pain: Tonic (conventional), amplitude modulation, pulse width modulation, sinusoidal rate modulation, and stochastic rate modulation. Results demonstrated that under the parameter settings tested in this study, all tested patterns except pulse width modulation, significantly reversed mechanical hypersensitivity, with stochastic rate modulation achieving the highest efficacy, followed by the sinusoidal rate modulation. The anti-nociceptive effects of sinusoidal rate modulation on EEG outlasted SCS duration on the behavioral and EEG levels. These results suggest that TDP modulation may improve clinical outcomes by reducing pain intensity and possibly improving the sensory experience. [ABSTRACT FROM AUTHOR]

Pain is known to disrupt sleep patterns, and disturbances in sleep can further worsen pain symptoms. Sleep spindles occur during slow wave sleep and have established effects on sensory and affective processing in mammals. A number of chronic neuropsychiatric conditions, meanwhile, are known to alter sleep spindle density. The effect of persistent pain on sleep spindle waves, however, remains unknown, and studies of sleep spindles are challenging due to long period of monitoring and data analysis. Utilizing automated sleep spindle detection algorithms built on deep learning, we can monitor the effect of pain states on sleep spindle activity. In this study, we show that in a chronic pain model in rodents, there is a significant decrease in sleep spindle activity compared to controls. Meanwhile, methods to restore sleep spindles are associated with decreased pain symptoms. These results suggest that sleep spindle density correlates with chronic pain and may be both a potential biomarker for chronic pain and a target for neuromodulation therapy. [ABSTRACT FROM AUTHOR]

T-type Ca channels (T channels), particularly Cav3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Cav3.1 or Cav3.2 by electrophysiological and fluorescent Ca signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of -65 ∼ -60 mV, but not -80 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K-induced Ca signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Cav3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury-induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. The analgesic and antihyperalgesic/antiallodynic doses of oral and i.p. RQ did not significantly affect the locomotor activity and motor coordination. Together, RQ is considered a state-dependent blocker of Cav3.1/Cav3.2 T channels and may serve as an orally available analgesic for treatment of neuropathic and inflammatory pain including distinct visceral pain with minimum central side effects.

In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex. Gamma oscillations in somatosensory areas in humans correlate with pain perception and pain stimulus intensity, but could also reflect cognitive processes such as attention. Here the authors provide evidence in mice that these oscillations causally contribute to pain perception. [ABSTRACT FROM AUTHOR]

We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats. [ABSTRACT FROM AUTHOR]