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ACTIVE SLEEP-RELATED MODULATION OF SPINORETICULAR TRACT NEURONS Spontaneous Spike Activity of Spinoreticular Tract Neurons During Sleep and Wakefulness Peter J. Soja, Walton Pang, Niwat Taepavarapruk, and Shelly A. McErlane Division of Pharmacology & Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada Abstract: Sleep mentation studies infer that pain sensation in humans may be reduced during active REM sleep. However, to provide a mechanistic explanation for this phenomenon, few, if any neurophysiological studies have been performed at the lumbar level from neurons comprising classical pain pathways during sleep and wakefulness. The spinoreticular tract is one such classical pathway that has been implicated in the rostral transmission of nociceptive information. The present study was performed to determine if the activity of spinoreticular tract (SRT) neurons is dependent upon behavioral state. Accordingly, extracellular recording techniques were used to monitor the activity of identified SRT neurons in unanesthetized chronic cats during sleep and wakefulness. The ongoing spike activity of SRT neurons was found to be relatively uniform when the states of quiet wakefulness and quiet sleep were compared. However, during active sleep, the majority of the SRT neurons sampled underwent a sustained reduction in spike activity. Marked facilitation of SRT cell activity occurred in a few instances. These data provide the first unitary evidence supporting earlier evoked potential, psychophysical and clinical studies that ascending sensory information in a classical pain pathway is regulated in a state-dependent fashion. Key words: Active sleep; dorsal horn; sensory; spinal cord; spinoreticular INTRODUCTION difficult to extrapolate from acute experimental preparations on exactly how or when descending controls act upon SRT neurons to modulate the rostral transmission of sensory nociceptive information. Earlier evoked potential studies by Pompeiano and his colleagues suggested that a variety of spinal sensory pathways whose axons project through the medial leminiscus are regulated only during the rapid eye movement (REM) portions of active sleep.14,15 We recently reported that sciatic nerve evoked field potentials recorded from fibers comprising the SRT and spinothalamic tracts (STT) are reduced throughout the state of active sleep and can even be abolished during the REM saccades associated with this state.16 These data support the idea that innocuous and nociceptive information conveyed by these ascending sensory pathways1 may be reduced both tonically and phasically during the behavioral state of active sleep. However, field potential experiments of this type are limited in that they do not distinguish precisely which sensory pathway is specifically regulated. Regulated pathways could include not only the SRT and STT but also other ascending pathways projecting amongst the fiber tracts within the ventrolateral reticular formation such as the spinomesencephalic tract and ventral spinocerebellar tract. These caveats notwithstanding, the only plausible approach to evaluate changes in transmission through each of these ascending sensory pathways is to record single unit activity from antidromically identified spinal cord neurons. The difficulty associated with this task depends in part on the feasibility of recording a particular type of ascending sensory tract neuron in chronically instrumented animal preparations.17 In acute anesthetized cats, SRT neurons are readily located in the upper lumbar segments within the ventral gray matter lateral as well as ventral to Clarke’s column DSCT neurons.2,10,18-20 We report herein that the THE SPINORETICULAR TRACT IS ONE OF SEVERAL CONSORTIUM SOMATOSENSORY TRACTS INVOLVED IN THE SENSORI-DISCRIMINATIVE ASPECTS OF PAIN AND TACTILE PROCESSING.1 Electrophysiological studies performed in acute anesthetized animal preparations have revealed that SRT neurons respond to intense electrical or natural stimulation of peripheral receptive fields.2-8 For example, studies performed by Ammons et al. and Fields et al. have shown that spinoreticular tract neurons can be driven by cutaneous nociceptors upon application of intense stimuli (e.g., pinch, or prick to their peripheral receptive fields).3,9 In addition, high intensity stimulation of peripheral nerves at intensities capable of recruiting unmyelinated C- fibers also excites SRT neurons in anesthetized animal preparations. Additionally, these forms of SRT neural excitation by nociceptive stimuli are controlled by supraspinal influences originating from a variety of sources such as the nucleus reticularis gigantocellualris and raphe magnus.10,11 In this regard, it has been reported that electrical stimulation of the NRGc or raphe magnus inhibits the discharge of SRT neurons responding to noxious stimuli.10,11 With respect to the latter, studies performed in acute anesthetized animal preparations, have applied phasic electrical stimulation paradigms to discrete brainstem centers and demonstrated complex facilitatory or inhibitory actions on recorded SRT neurons.10-13 However, it is Accepted for publication November 2000 Address correspondence to: Peter J. Soja, PhD, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3 CANADA; Tel: 604-822-2692; Fax: 604-822-4609; E-mail: [email protected] SLEEP, Vol. 24, No. 1, 2001 18 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al Figure 1—Methods used to antidromically identify L3 SRT neurons. The vertical calibration bar to 75µV for EEG, EOG, PGO, and EMG traces. A. Experimental scheme of lumbar recording and brainstem stimulation sites. B. Oscilloscope trace illustrating SRT neuron spontaneous spike activity and typical signal-to-noise ratio. C. Three superimposed oscilloscope traces are presented of an antidromic action potential recorded in L3 spinal cord segment after stimulation of the contralateral, ventrolateral reticular formation using a single pulse (80 A, 0.2 msec, 1 Hz). D. High-frequency (500 Hz, 2 pulses) train of stimuli. The asterisks in C and D denote the stimulus onset. Consecutive antidromic responses displayed constant latency-to-onset indicating that the action potential resulted from antidromic activation of the axon of the recorded unit. E. Single oscilloscope sweeps illustrating a collision between the antidromic and a spontaneous action potential. The sweeps are aligned by the onset of reticular stimuli (asterisks) as indicated by the dashed vertical line. The lower oscilloscope sweep in E illustrates a collision between an orthodromically activated action potential evoked by stimulation of the reticular formation (0.2 msec, 80 A) and the antidromic spike. Animals were allowed to fully recover over a three-month period following these surgical implant procedures during which time they were gradually trained to accept painless stereotaxic head and lumbar restraint.22 Animals were loosely wrapped in a soft canvas bag and subsequently positioned in a heavy duty Kopf stereotaxic frame. The previously implanted head and lumbar restraining devices were affixed to the stereotaxic AP bars by Kopf chronic holding devices (Model 880). Animals were able to make postural limb adjustments during head and lumbar restraint. All surgical and chronic restraint procedures reported complied with (inter) national25,26 and institutional (University of British Columbia Animal Care Committee) guidelines. Further details of these implant and restraint procedures were reported previously.22 activity of individual SRT neurons in the chronic unanesthetized cat preparation is indeed dependent on behavioral state. These data may have relevance to psychological studies whereby reports of experimental or spontaneous pain are diminished or absent during active sleep. Preliminary results have been reported elsewhere.21 METHODS Surgical Procedures Adult cats were prepared for extracellular unit recording of spinal cord neurons during sleep and waking states using previously established methods.22 Four intact, unanesthetized, chronically instrumented cats were implanted under deep gaseous anesthesia (45-60% N20 in 1.5-2.5% halothane/oxygen mixture) with head and lumbar restraining devices. Electrodes were also implanted into the frontal sinus (electroencephalogram [EEG]), lateral geniculate nucleus of the thalamus (ponto-geniculo-occipital [PGO] wave activity), the orbital plate (electro-oculogram [EOG]) and neck muscles (electromyogram [EMG]) and were used for monitoring behavioral states. Through the use of these electrodes, the animal’s behavioral states of wakefulness, quiet sleep and active sleep could be determined when spinoreticular tract neurons were being located and recorded.22-24 In addition to these electrodes, chronic restraining devices composed of acrylic resin were fixed to the skull and lower lumbar vertebrae L2-L6. SLEEP, Vol. 24, No. 1, 2001 Stimulation and Recording Procedures Glass microelectrodes containing a carbon fiber27 that were backfilled with 4M NaCl were used to record from L3 spinal cord neuronal elements using an AC-coupled amplifier (AM-Systems Model 1800). Amplified signals (1000X, bandpass, 0.3-10 KHz) were routed to a window discriminator, rate counter (Digitimer, Inc.), and oscilloscope. Recording electrodes were slowly lowered in tracks beginning 0.2-0.7 mm lateral to the midline of the L3 spinal cord. Low-intensity search stimuli were applied to a stimulating electrode (A-M Systems, Cat. # 5755, 5-8 MΩ, AC) that was stereotaxically positioned (HC: P10, L3.5 to 4.0, H –8.0 19 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al to –8.5) in the contralateral ventrolateral reticular formation immediately below the facial motor nucleus16 in order to “backfire” L3 neurons. Previous studies performed in acute anesthetized cats have indicated that spinoreticular neurons are predominantly recorded in lower thoracic and upper lumbar spinal cord segments at spinal cord depths corresponding to lamina V and VII,28 dorsolateral and ventral, respectively, to Clarke’s Column.9,18 Accordingly, neurons were targeted in this area and well-isolated (signal-tonoise ratios >3.0) cells were systematically checked for ascending axonal projections (Figure 1). Criteria for antidromic activation were similar to those used previously for dorsal spinocerebellar tract (DSCT)22 or trigeminothalamic tract (TGT)24 neurons and included constant latency spikes evoked by consecutive lowintensity monopolar stimuli (0.2 ms, 0.5 Hz, 100-250 A) the ability to faithfully follow a short train of high frequency stimuli, and collision with spontaneous action potentials.22,24 spike amplitude. The average spontaneous firing rate (spikes/s, Hz) was calculated for each neuron using trains of 500-1000 consecutive spikes. In two cells the firing rate was substantially reduced during active sleep (see Results). For these neurons, a minimum of 50 consecutive spikes was used to determine average spontaneous spike rate during active sleep. Data obtained during quiet wakefulness following active sleep served as control for comparison with data obtained during quiet sleep, and the middle portion of active sleep. For spike rate, differences between control and test (wakefulness, quiet sleep, and active sleep) states were plotted and analyzed for statistical significance using a repeated measures ANOVA, (SigmaPlot 2000, SigmaStat, SPSS Inc.) with α set at 0.05. Spike interval data were also described using interspike interval histograms (ISIH) and quantified using the following parameters: mean interval (reciprocal of firing rate), coefficient of dispersion (CD= variance / mean interval) and coefficient of variation (CV = standard deviation / mean interval).29 Spike rate and ISIH parameters were expressed as group mean values±SEM. Data Analyses A Pentium III microcomputer equipped with spike acquisition and analysis software (SPIKE 2-v.3-01, 1401plus, Cambridge Electronic Design, Inc.) was used for quantifying neuronal data. A subroutine was employed to sort spike templates and verify that the same SRT neuron was recorded across all behavioral states. Accepted spikes did not deviate by 15% in peak-to-peak RESULTS SRT Neurons, General Properties Extracellular recordings were obtained from a total of fifteen antidromically identified SRT neurons located at an average in situ recording depth of 3,320 microns (range: 2,480-4,500) Figure 2—Suppression of a spinoreticular tract neuron activity during active sleep. The first four traces depict the behavioral state of the animal, as indicated by the cortical electroencephalogram (EEG), electro-oculogram (EOG), ponto-geniculo-occipital (PGO) wave, and electromyogram (EMG) activities. Below the four electrophysiological signals, a continuous rate-meter trace represents discharge of the cell during the state of quiet sleep (QS), the transition into and throughout active sleep (AS) and re-awakening (RW). A sliding average (gray line, binwidth: 30s) is superimposed over the rate histogram trace. Note that spontaneous spike activity is nearly abolished during the state of active sleep when compared to quiet sleep and re-awakening. SLEEP, Vol. 24, No. 1, 2001 20 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al Figure 3—Facilitation of a spinoreticular tract neuron activity during active sleep. The first four traces in represent behavioral state and the bottom trace represents SRT neuronal activity as indicated in Figure 1. Note that during active sleep, the cell underwent phasic periods of excitation. The sliding average (gray line, bin width: 30s) indicates the overall increased excitability of this cell during active sleep. below the surface of the spinal cord. Several factors contribute to the problem of determining the precise in situ spinal laminar locations of recorded neurons. These include but are not limited to unavoidable errors associated with obtaining accurate micrometer depth readings from the surface of the spinal cord due to inherent dead space in pneumatic microdrive apparatus and/or continuous presence of cerebrospinal fluid on the spinal cord surface. This uncertainty is inevitable despite conscientious efforts to minimize these factors (see also reference 30). Mean antidromic latencies taken from the beginning of the stimulus artifact to the initiation of the action potential measured 3.2 ms ± 0.5, (range: 2.1-4.4) at threshold (mean: 106 µA±7, range: 20-230) stimulus intensities. The mean conduction velocities were estimated at 86.8 m/s±15.5 (range: 60.2-120m/s). Each neuron displayed constant latency antidromic spikes with no jitter, faithfully followed short high frequency (500Hz) stimulus trains and demonstrated collision between antidromically propagated and spontaneously occurring action potentials (Figure 1). For all cells, antidromic spikes were evoked from the contralateral reticular formation. In our recording experiments, it was not possible to test for bilateral projections of recorded cells due to space constraints involving positioning of stereotaxic hardware. The animals never displayed any signs of discomfort such as EEG desynchronization, hissing, or vocalization during these identification procedures. SRT neurons recorded in the L3 spinal segment of the chronic unanesthetized cat preparation display moderate rates of sponSLEEP, Vol. 24, No. 1, 2001 taneous spike activity, which, as reported below, was dependent on the animal’s behavioral state. An example of the spontaneous firing rate of an antidromically identified SRT neuron is shown in Figure 1B. SRT neurons also displayed broad cutaneous receptive fields encompassing the animal’s ipsilateral flank, proximal tail, and hind limb areas. Most SRT neurons recorded in the unanesthetized cat displayed phasic robust burst discharge to innocuous forms of receptive field stimuli such as air puff induced hair movement, and light stroking of cutaneous receptive fields. Stroking and air puff were induced using a hand held soft camel hair brush or glass pipette fitted with a bulb. Such stimuli do not provide for quantifiable data as reliably as mechanically controlled forms of stimulation (e.g., reference 23). In several cases, oligosynaptic responses could also be recorded following low-intensity stimulation of the sciatic nerve. These and other data involving mechanically controlled forms of stimulation are currently in progress and will be described in detail elsewhere. Spontaneous Spike Activity During Wakefulness, Quiet Sleep, and Active Sleep The state of quiet wakefulness was characterized by a desynchronized cortical EEG pattern, tonic EMG activity, sparse or no PGO and EOG activity, and little or no postural movements (Figures 2, 3). During quiet wakefulness, the average spontaneous discharge rate of all 15 SRT neurons measured 21.1 spikes/s±3.9 (range: 4.7-58.9). The state of quiet sleep differs 21 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al Figure 4—Bar graphs summarizing the direction and magnitude of change in spike activity for 15 SRT neurons recorded across the sleep or wake cycle. Y axis represents facilitation or suppression during active sleep when compared to quiet wakefulness. Each bar represents the relative change for each SRT neuron. from quiet wakefulness principally by the presence of a large amplitude synchronized slow-wave EEG pattern, a relatively moderate level of EMG activity, and little or no EOG and PGO wave activity (Figures 2, 3). The group mean spontaneous spike rate for the same SRT neurons measured 19.1 spikes/s±3.5 (range: 5.2-41.4) and did not significantly differ from values obtained during quiet wakefulness, (p>0.05). The state of active sleep is hallmarked by EEG desynchrony, muscle atonia, robust PGO wave activity, and EOG activity (Figures 2, 3). During this state, the ongoing spike activity of all SRT neurons was reduced to 14.7 spikes/s±3.1 (p<0.05, range: 0.5-38). When compared to the state of quiet wakefulness, this corresponds to a 31% decrease in SRT neuronal activity. During active sleep, there was a greater than 25% decrease in spike rate in eight cells and an increase in two cells. Examples of suppression and facilitation of SRT neuron spike activity during active sleep are illustrated in Figures 2 and 3, respectively. Note that for each example, the change in firing rate occurs only during active sleep. Figure 4 illustrates the relative change in cellular activity during active sleep for each cell. Analyses of interspike interval histograms (ISIH) across all SRT neurons revealed that the pattern of spike firing was relatively constant during quiet wakefulness and quiet sleep. Individual interspike interval distributions of SRT neuronal activity constructed during quiet sleep and wakefulness were leptokurtic, and positively skewed (Figure 5). Indeed, they closely resembled those corresponding to the same behavioral states from a previous study of dorsal spinocerebellar tract neurons.30 In the present study, this was confirmed by measuring no significant difference in the group mean values for coefficient of dispersion (CD) and variation (CV) of interspike intervals when quiet wakefulness was compared with quiet sleep (p>0.05; CDQUIET WAKEFULNESS: 0.05±0.01, range: 0.003-0.14; CDQUIET SLEEP: SLEEP, Vol. 24, No. 1, 2001 0.08 ± 0.03, range: 0.007-0.42; CVQUIET WAKEFULNESS: 0.96±0.21, range: 0.39-3.25; CVQUIET SLEEP: 0.75±0.08, range: 0.27-1.33). Moreover, the group mean interspike intervals did not differ (p>0.05). However, during active sleep, ISIH distributions were broader and markedly asymmetric due to considerably fewer SRT action potentials during this state (Figure 5). Accordingly, there was a significant increase in the CD and CV values by factors of 4.2 and 1.7, respectively (p<0.05; CDACTIVE SLEEP: 0.21±0.04, range: 0.01-0.54; CVACTIVE SLEEP: 1.27±0.16, range: 0.75-3.25). Predictably, when compared to quiet wakefulness, the group mean interspike interval during active sleep was also increased by a factor of 1.4 (p<0.05). During active sleep, rapid eye movement (REM) saccades often occurred in conjunction with a burst of PGO waves and were further associated with complex changes in SRT neuron spike activity. An example of both facilitation and suppression of SRT neuron activity around REM saccade events is illustrated in Figure 3. In this particular example, the firing rate of the cell was facilitated during active sleep. Further details of the modulation of SRT neuron spike activity REM saccades will be reported elsewhere. DISCUSSION The present study utilized conventional extracellular recording methods in the chronic unanesthetized cat to monitor the spike discharge of antidromically identified SRT neurons during states of sleep and wakefulness SRT neurons recorded in the present study were antidromically activated using discrete microstimuli applied to the ventrolateral reticular formation. Backfired SRT neurons had a mean axonal conduction velocity (86.8 m/s) similar to that of DSCT neurons (81.1 m/s) and were recorded somewhat deeper to DSCT 22 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al Figure 5—Interspike interval histograms (ISIHs) for an SRT neuron recorded during wakefulness, quiet sleep, and active sleep. Each ISIH was constructed from 1000 consecutive spikes. Compared with wakefulness and quiet sleep, ISIHs constructed during and AS are reduced in amplitude and skewed to the right. This reduction in amplitude is due to the reduced firing rate while the skewing of the ISIH is a result of longer pauses in the firing pattern. Above each ISIH is the median interval, and coefficients of dispersion (CD) and variation (CV) describing the interspike intervals in each ISIH. The increased coefficient of variation in active sleep as compared with wakefulness or quiet sleep further confirms the irregular pattern of spike discharge during active sleep. Spike train patterns over 2 s epochs derived from each behavioral state are also shown. neurons in the L3 spinal gray matter.30 However, the mean axonal conduction velocity of SRT neurons in the present study is reported to be approximately two times faster than SRT neurons recorded more dorsolaterally in the spinal gray matter of acute anesthetized animal preparations17-19 and likely reflects different classes of SRT neurons in the spinal gray.1 While both SRT and DSCT neurons display robust and regular spike activity during SLEEP, Vol. 24, No. 1, 2001 the state of wakefulness and quiet sleep, SRT neurons recorded in the acute, paralyzed and anesthetized animal preparation exhibit much lower (1-8 spikes/s) spontaneous firing rates than those reported in the present study, presumably due to the direct suppressant actions of anesthetic agents such as α-chloralose.31,32 The principal finding of the present study is that SRT neuronal activity is dependent on behavioral state. The direction, magni23 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al tude and pattern of state dependent modulation are similar to that which occurs for Clarke’s Column DSCT neurons recorded in the L3 segment.33 These data may provide a cellular correlate to our previous evoked potential studies where sciatic nerve-evoked field responses recorded from the SRT fiber tract were reduced or even abolished during the state of active sleep.16 Given the well established evidence that the SRT is a major sensory channel conveying tactile and pain information to higher brain centers,1,9,18,19,34 our data also provide a neurophysiological basis for clinical observations that thermal pain sensations, per se, may be dampened during sleep when compared to wakefulness35 (see also reference 36). The present study imposed strict ethical constraints whereby the responsiveness of SRT neurons to peripherally applied forms of noxious stimuli could not be undertaken. Hence it was not possible to verify that the sample of SRT neurons we recorded from actually relay nociceptive information suprapsinally. However, given that L3 SRT neurons recorded in acute anesthetized animals respond to nociceptive stimulation of their peripheral receptive fields, it is likely that certain SRT cells recorded in the present study were nociceptive. The ability to obtain stable recordings of individual SRT neurons located in the upper lumbar segments in the chronic cat preparation across behavioral states, such as sleep and wakefulness, will further enhance opportunities for investigating the interactions between sleep and pain without the confounding distorting suppression caused by general anesthetics32 and/or recent surgery.37 Additional unit recording studies of SRT and other spinal projection (e.g., spinothalamic tract, neurons driven submaximally by specific receptors such as thermoreceptor and/or hair mechanoreceptors during the sleep/wake cycle) are required to corroborate these35 and other findings.38,39 Indeed, other lines of evidence suggest that during active sleep sensory gating of small vs. large diameter input occurs at higher neuraxial levels, in particular, the trigeminal sensory nuclear complex.24,40 Neurotransmitters released from afferent terminals onto spinal projection neurons include substance P and glutamate. Both agents are known to exert potent postsynaptic excitations of spinal cord sensory tract neurons.41-43 SRT neurons may be subjected to state-dependent modulatory influences that counteract the actions of primary afferent neurotransmitters. In this regard, we recently reported that the glutamate-evoked responses of SRT neurons were reduced during the state of active sleep when compared to quiet sleep or wakefulness.44 Hence it is possible that the reduction of sensory transmission through the SRT during active sleep is partly dependent on direct postsynaptic inhibition of L3 cells. However, the pharmacological basis for reduced glutamate responsiveness of SRT neurons during active sleep is not known. Another mechanism for reduced SRT neuron activity during active sleep may include the induction via higher brain centers of presynaptic mechanisms regulating transmitter release at synapses between primary afferent and recorded SRT neurons.45 Such processes could also occur at synapses upstream such as between SRT axon terminals and recipient third order reticular formation cells.17,46 In this relatively small sample of SRT neurons recorded to date, inhibition was the predominant effect observed during active sleep. A few cells were also markedly facilitated. Facilitation of spike activity may arise as a result of disinhibitory processes and/or direct postsynaptic excitatory drives to SRT neurons. The possibility remains that further sampling of (venSLEEP, Vol. 24, No. 1, 2001 tral vs. dorsolateral) SRT neurons during wakefulness vs. active sleep may yield clearly distinct subclasses (i.e., facilitated and/or inhibited SRT neurons). Indeed, antecedent experiments performed in the acute anesthetized animal preparation have demonstrated distinct supraspinal facilitatory and inhibitory influences on SRT neurons following phasic electrical stimulation of the medullary reticular core.5 In summary, the results of the present study imply that ongoing sensory transmission conveyed to higher brain centers via the SRT may be regulated in a state-dependent fashion. Multiple mechanisms may be engaged at spinal and supraspinal sites to afford suppression (and facilitation) of synaptic transmission including pain through this sensory pathway. ACKNOWLEDGMENTS This work was supported by a grant from the U.S. National Institutes of Health (NS 34716). W. Pang was supported by Pharmaceutical Manufacturer’s Association of Canada/Medical Research Council of Canada (PMAC/MRC) Studentship in Pharmacy. N. Taepavapruk was supported by a Thai Government Graduate Fellowship. REFERENCES 1. Willis WD, Coggeshall RE. Sensory Mechanisms of the Spinal Cord. Second ed. New York: Plennum Press, 1991. 2. Ammons WS. Responses of spinoreticular cells to graded increases in renal venous pressure. Am J Physiol 1991;260:R27-31. 3. Fields HL, Clanton CH, Anderson SD. Somatosensory properties of spinoreticular neurons in the cat. Brain Res 1977;120:49-66. 4. Foreman RD, Blair RW, Weber RN. Viscerosomatic convergence onto T2-T4 spinoreticular, spinoreticular- spinothalamic, and spinothalamic tract neurons in the cat. Exp Neurol 1984;85:597-619. 5. Haber LH, Moore BD, Willis WD. Electrophysiological response properties of spinoreticular neurons in the monkey. J Comp Neurol 1982;207:75-84. 6. Maunz RA, Pitts NG, Peterson BW. Cat spinoreticular neurons: locations, responses and changes in responses during repetitive stimulation. Brain Res 1978;148:365-79. 7. Menetrey D, de Pommery J, Besson JM. Electrophysiological characteristics of lumbar spinal cord neurons backfired from lateral reticular nucleus in the rat. J Neurophysiol 1984;52:595-611. 8. Sahara Y, Xie YK, Bennett GJ. Intracellular records of the effects of primary afferent input in lumbar spinoreticular tract neurons in the cat. J Neurophysiol 1990;64:1791-800. 9. Ammons WS. Renal and somatic input to spinal neurons antidromically activated from the ventrolateral medulla. J Neurophysiol 1988;60:1967-81. 10. Chapman CD, Ammons WS, Foreman RD. Raphe magnus inhibition of feline T1-T4 spinoreticular tract cell responses to visceral and somatic inputs. J Neurophysiol 1985;53:773-85. 11. Cervero F, Wolstencroft JH. A positive feedback loop between spinal cord nociceptive pathways and antinociceptive areas of the cat’s brain stem. Pain 1984;20:125-38. 12. McCreery DB, Bloedel JR. Reduction of the response of cat spinothalamic neurons to graded mechanical stimuli by electrical stimulation of the lower brain stem. Brain Res 1975;97:151-6. 13. Bloedel JR, McCreery DB. Organization of peripheral and central pain pathways. Surg Neurol 1975;4:65-81. 14. Carli G, Kawamura H, Pompeiano O. Transmission of somatic sensory volleys through ascending spinal hindlimb pathways during sleep and wakefulness. Pflugers Arch 1967;298:163-9. 15. Pompeiano O, Carli G, Kawamura H. Transmission of sensory 24 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al information throug ascending spinal hindlimb pathways during sleep and wakefulness. Arch Ital Biol 1967;105:529-72. 16. Soja PJ, Oka JI, Fragoso M. Synaptic transmission through cat lumbar ascending sensory pathways is suppressed during active sleep. J Neurophysiol 1993;70:1708-12. 17. Soja PJ, Cairns BE, Kristensen MP. Transmission through ascending lumbar sensory pathways: Dependence on behavioral state. In: Lydic R, Baghdoyan H, eds. Handbook of behavioral state control—cellular and molecular mechanisms. Boca Raton, FL: CRC Press, 1999:521-44. 18. Ammons WS. Characteristics of spinoreticular and spinothalamic neurons with renal input. J Neurophysiol 1987;58:480-95. 19. Ammons WS. Spinoreticular cell responses to intrarenal injections of bradykinin. Am J Physiol 1988;255:R994-1001. 20. Blair RW, Ammons WS, Foreman RD. Responses of thoracic spinothalamic and spinoreticular cells to coronary artery occlusion. J Neurophysiol 1984;51:636-48. 21. McErlane SA, Kristensen MP, Soja PJ. Spike activity of spinoreticular tract neurons during wakefulness and sleep. Soc Neuroscience Abst 1997;23:2341. 22. Soja PJ, Fragoso MC, Cairns BE, Oka JI. Dorsal spinocerebellar tract neuronal activity in the intact chronic cat. J Neurosci Methods 1995;60:227-39. 23. Ursin R, Sterman MB. A manual for standardized scorin of sleep and waking statesin the adult cat. Los Angeles, CA: Brain Information Service, University of California, 1981. 24. Cairns BE, McErlane SA, Fragoso MC, Jia WG, Soja PJ. Spontaneous discharge and peripherally evoked orofacial responses of trigemino-thalamic tract neurons during wakefulness and sleep. J Neurosci 1996;16:8149-59. 25. Canadian Council on Animal Care. Guide to the care and use of experimental animals. Second ed. Ottawa, CANADA: Bradda Printing Services, 1993. 26. National Research Council. Guide for the care and use of laboratory animals. Washington, DC: National Academy Press, 1996. 27. Armstrong-James M, Millar J. Carbon fibre microelectrodes. J Neurosci Methods 1979;1:279-87. 28. Rexed BA. The cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 1954;100:297-380. 29. Cocatre-Zilgien JH, Delcomyn F. Identification of bursts in spike trains. J Neurosci Methods 1992;41:19-30. 30. Soja PJ, Fragoso MC, Cairns BE, Jia WG. Dorsal spinocerebellar tract neurons in the chronic intact cat during wakefulness and sleep: analysis of spontaneous spike activity. J Neurosci 1996;16:1260-72. 31. Collins JG, Kawahara M, Homma E, Kitahata LM. Alpha-chloralose suppression of neuronal activity. Life Sci 1983;32:2995-9. 32. Taepavarapruk N, McErlane SA, Pang W, Soja PJ. Spinoreticular tract neurons: a comparison of activity during wakefulness vs. thiopental anesthesia. Soc Neuroscience Abst 1997;23.:2341. 33. Cairns BE, Fragoso MC, Soja PJ. Active-sleep-related suppression of feline trigeminal sensory neurons: evidence implicating presynaptic inhibition via a process of primary afferent depolarization. J Neurophysiol 1996;75:1152-62. 34. Ammons WS. Renal afferent input to thoracolumbar spinal neurons of the cat. Am J Physiol 1986;250:R435-43. 35. Lavigne G, Zucconi M, Castronovo C, Manzini C, Marchettini P, Smirne S. Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems. Pain 2000;84:283-90. 36. Velluti RA. Interactions between sleep and sensory physiology. J Sleep Res 1997;6:61-77. 37. Li HS, Monhemius R, Simpson BA, Roberts MH. Supraspinal inhibition of nociceptive dorsal horn neurones in the anaesthetized rat: tonic or dynamic? J Physiol (Lond) 1998;506:459-69. 38. Symons D. The stuff that dreams aren’t made of: why wake-state and dream-state sensory experiences differ. Cognition 1993;47:181-217. 39. Nielsen TA, McGregor DL, Zadra A, Ilnicki D, Ouellet L. Pain in SLEEP, Vol. 24, No. 1, 2001 dreams. Sleep 1993;16:490-8. 40. Cairns BE, Fragoso MC, Soja PJ. Activity of rostral trigeminal sensory neurons in the cat during wakefulness and sleep. J Neurophysiol 1995;73:2486-98. 41. Nahin RL. Immunocytochemical identification of long ascending peptidergic neurons contributing to the spinoreticular tract in the rat. Neuroscience 1987;23:859-69. 42. Willcockson WS, Chung JM, Hori Y, Lee KH, Willis WD. Effects of iontophoretically released peptides on primate spinothalamic tract cells. J Neurosci 1984;4:741-50. 43. Dougherty PM, Willis WD. Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P. Pain 1991;47:85-93. 44. Kristensen MP, Pang W, Taepavarapruk N, McErlane SA, Soja PJ. Spike activity of spinoreticular tract neurons evoked by glutamate microiontophoresis or peripheral nerve stimulation during wakefulness and sleep. Ninth World Congress on Pain, Vienna 1999;9:169. 45. Martin RF, Haber LH, Willis WD. Primary afferent depolarization of identified cutaneous fibers following stimulation in medial brain stem. J Neurophysiol 1979;42:779-90. 46. Cairns BE, Soja PJ. Active sleep-related depolarization of feline trigemino-thalamic afferent terminals. Neuroreport 1998;9:565-7. 25 Active Sleep-related Modulation of Spinoreticular Tract Neurons—Soja et al