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REPORT
Atkinson Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona 85013
Submitted 15 April 2004; accepted in final form 21 May 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Price et al. 2003). Proponents of the widely held pattern/intensity concept of pain sensation profess that WDR lamina V STT neurons (the "pain transmission" cells of gate control theory; Wall 1973) are "necessary and sufficient" for all types of pain sensation and that their discharge "encodes" pain (Price et al. 2003; Willis and Westlund 1998). Notably, even investigators who recognize a critical role for substance P–responsive lamina I neurons suppose that they contribute to pain sensation by modulating the activity of WDR lamina V STT cells (Hunt and Mantyh 2001; Khasabov et al. 2002).
However, the evidence supporting a role of WDR lamina V cells in pain sensation is tenuous, and there are numerous fundamental incongruities (Craig 2003). The most obvious is the inherent modality ambiguity of lamina V WDR cells. Whether considered singly or as a population, their intensity-related discharge cannot differentiate stimulus modality or tissue of origin, whereas human sensation certainly does both (Carstens 1997; Craig 2003; Lewis 1942; Perl 1984). In contrast, evidence in cats indicates that the activity of nociceptive-specific (NS) lamina I STT cells, dominated by A
-fiber input, and polymodal nociceptive (HPC, for heat, pinch, and cold) lamina I STT cells, dominated by C-fiber input, can differentially signal the distinct sensations of sharp (1st) and burning (2nd) pain, respectively (Andrew and Craig 2002; Craig and Andrew 2002). However, Price et al. (2003) recently claimed that such evidence is inconclusive and reiterated their view that WDR neurons are essential for pain. Clearly, a direct comparison of the responses of lamina I and lamina V STT cells in the monkey with the psychophysical profile of a discriminating test of human pain sensation is needed.
A discriminating test is provided by the repeated brief-contact heat paradigm of Vierck et al. (1997), in which a hot probe briefly (0.7 s) contacts the skin repeatedly at interstimulus intervals (ISIs) of 2–5 s. This stimulus selectively elicits in human subjects a strongly augmenting sensation of burning pain, and only a weak sensation of sharp pain, with a characteristic temporal profile and dependence on ISI and temperature. Most strikingly, it displays a unique "reset" phenomenon, in which the omission of one or two stimuli in a train of brief contacts causes the pain to suddenly disappear and the temporal augmentation to begin again from near baseline (indicating that the augmentation is a central process, perhaps a disinhibition, that is not directly related to skin temperature). We previously showed that this paradigm (and alternatively, a graded series of sharp points) differentiates NS and HPC lamina I STT neurons in cats (Andrew and Craig 2002; Craig and Andrew 2002). This test was used in this study to directly compare lamina I and lamina V STT cells in monkey. A preliminary report was made at the 2003 meeting of the Society for Neuroscience.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). The methods conform with the animal welfare guidelines of the National Institutes of Health and the American Physiological Society, and they were approved by the local institutional review board. The animals were anesthetized with intravenous pentobarbital (bolus 40 mg/kg; 
10 mg/kg/h) following induction with intramuscular ketamine (10 mg/kg). Blood pressure, rectal temperature, and end-tidal CO2 were monitored and stabilized, the animal was placed in a stereotaxic holder, and dexamethasone (10 mg) and a muscle paralytic (pancuronium bromide, 400 µg/h) were administered. Based on microelectrode localization of somatosensory thalamus and the posterior ventromedial nucleus (VMpo), an array of five bipolar electrodes was inserted in the right thalamus to antidromically identify STT neurons. The electrodes were aimed at major spinothalamic projection targets in medial and lateral thalamus (i.e., MDvc, CL, VMpo, VPI, and VPL, as described further by Dostrovsky and Craig 1996). Each cell was tested from all electrodes.
A dorsal laminectomy was made, and single lumbosacral STT units were recorded on the left side with tungsten-in-glass microelectrodes and characterized with natural stimulation as before (Andrew and Craig 2002; Dostrovsky and Craig 1996). All units had receptive fields on the distal hindlimb, generally the calf, ankle, or foot. Lamina I STT units were obtained at depths of 200–500 µm and lamina V STT units at depths of 700–1,300 µm (see Fig. 1). Lamina I neurons were classified as NS if they responded to noxious pinch, noxious heat, or both, but not to low-threshold mechanical or thermal stimulation, and they were classified as HPC neurons if they responded to noxious pinch, heat, and noxious cold, but not to low-threshold mechanical stimulation using thermoneutral probes, and were not inhibited by warming. ("Response" here means a stimulus-locked, reproducible increase in discharge that was audibly and visually several times greater than the range of variance in ongoing activity; see Craig et al. 2001 for quantitative data on the responses of such cells). All cells were characterized with standard, quantitative mechanical and thermal stimuli, including changes in limb position (Craig 2003; Dostrovsky and Craig 1996).
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). Skin contact dwell time was 0.7 s. The thermode was preheated to one of five temperatures (34.0, 46.6, 49.0, 51.4, or 54.8°C, measured at the skin-thermode interface after thermocouple stabilization for command temperatures of 34, 48, 51, 54, and 58°C; for further measurement details, see Craig et al. 2001), presented in ascending sequence, and for each temperature, three trains of 12 brief-contact stimuli were applied, one each at 5-, 3-, and 2-s ISIs, in that order, with 3 min between each train. Trials were occasionally repeated (with reversed ISI order) to verify reproducibility. Units that showed brisk responses to repeated brief-contact heat stimuli at 51.4°C were not always tested with the 54.8°C stimulus (to limit skin damage). The reset phenomenon was tested by following a 2-s ISI trial at the highest temperature by another trial at the same ISI, using a manually controlled intertrial interval (ITI) of 6 s (i.e., by skipping 2 contacts).
The data were stored and analyzed on a PC using a Power1401 and the program Spike2 (Cambridge Electronic Design, Cambridge, UK). Unit spikes were summed in bins corresponding to ISI and analyzed as before (Craig and Andrew 2002). Population means were normalized with respect to maximum discharge rate and compared statistically using the program SigmaStat/SigmaPlot (SPSS, Chicago, IL). Spinal recording sites were marked with lesions (current density, 40 µA-s) and identified histologically in serial thionin-stained 60-µm-thick transverse sections.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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), and two were also activated from intralaminar thalamus.
Three NS lamina I STT neurons [mean antidromic latency, 30.7 ± 6.4 (SD) ms] showed weak or no responses to repeated brief-contact heat, regardless of their responsiveness to noxious heat stimulation. Because this was the same as observed in the cat (Craig and Andrew 2002), such neurons were not studied further.
Nine HPC lamina I STT neurons (mean antidromic latency, 37.3 ± 17.8 ms) were studied. All showed augmenting responses to repeated brief-contact heat. Their individual responses resembled the characteristic temporal profile and had the same nonlinear dependence on temperature and inverse relationship with ISI seen in cat and in human subjects (Craig and Andrew 2002; Vierck et al. 1997). That is, at a high temperature and a 2-s ISI, each showed strong temporal augmentation between the 4th and 10th application of the hot thermode. In addition, each of seven HPC cells tested showed the reset phenomenon (Fig. 2, bottom left), in which the omission of two brief-contacts between two trials of stimuli presented at 2-s ISI produced an immediate reduction of the discharge to near baseline that was maintained for the initial contacts of the second trial and followed by a renewed temporal augmentation. This pattern is depicted well by the representative unit and the average normalized response of the entire ensemble of HPC lamina I STT neurons shown in Fig. 2 (left).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The observed response characteristics of monkey HPC lamina I STT neurons correspond very well with the characteristics of the burning pain sensation elicited in human subjects by repeated brief-contact heat. That is, they show the same temporal profile of augmentation with the same dependence on temperature and inverse relationship with ISI seen previously in the cat (Craig and Andrew 2002). Most convincingly, they show the same reset phenomenon. These data firmly support the view that the activity of C-fiber–responsive polymodal nociceptive lamina I STT neurons provide a virtual labeled line that is integrated with thermosensory activity in the forebrain to generate the sensation and the motivation associated with burning pain (Craig 2003). This is consistent with prior data indicating that HPC lamina I STT cells uniquely and quantitatively explain the burning pain elicited by the thermal grill illusion (using interlaced innocuous warm and cool stimuli) and the burning pain elicited by cutaneous heat, pinch, and cooling (<24°C) during a peripheral nerve block of A-fiber conduction in humans.
These data are consonant with the emerging concept that lamina I in primates provides a phylogenetically novel spinothalamocortical pathway (a forebrain extension of the homeostatic afferent pathway), highly developed in humans, that engenders several distinct, highly resolved sensations (feelings), which represent the physiological condition of the body (i.e., interoception redefined) and generate homeostatic emotions (Craig 2003). Proponents of the conventional view recently suggested that this lamina I pathway could not explain the haptic (discrimination and localization) capacities of cutaneous pain sensation, which they argued require WDR lamina V STT input to somatosensory thalamus and cortex (without explaining how such neurons distinguish different types of pain: Price et al. 2003). However, their argument ignored the available physiological, anatomical, and imaging data demonstrating that the lamina I STT pathway to the dorsal posterior insula is the unique and critical pathway for cutaneous temperature sensation (traditionally also regarded as exteroceptive), which means that this pathway certainly has the capacity to engender discriminative and well-localized sensations (Craig 2003; Craig et al. 2000). Significantly, both nociceptive and thermoreceptive lamina I STT neurons have small cutaneous receptive fields, are topographically organized, and display quantitative properties that correspond well with human psychophysical capacities; furthermore, imaging and evoked potential data strongly support the primary role of dorsal posterior insular cortex in temperature, pain, itch, muscle ache, sensual touch, and other well-discriminated feelings from the body (Craig 2003). The anatomical organization of the lamina I interoceptive pathway reflects the primal function of the small-diameter primary afferents that subserve human temperature and pain sensations, which is homeostasis and the control of autonomic activity (i.e., smooth muscle). The relationship of nociceptive activity to somatic motor (striate muscle) responses, on the other hand, probably involves the ancillary nociceptive lamina I input to area 3a of sensorimotor cortex, which parallels the input to area 3a from visceral afferents (Ito and Craig 2003). Imaging and recording data indicate that this area shows augmenting responses to repeated brief-contact heat (Tommerdahl et al. 1996), and it might also have a role in perception, though that remains to be elucidated.
Lamina V WDR activity does not correspond with burning pain
In contrast, the present results demonstrate that the activity of WDR lamina V STT neurons is distinctly different from the profile of human burning pain sensation. That is, during the characteristic period when humans report augmenting pain to repeated brief-contact heat, WDR lamina V cells immediately display a plateau of maintained activity, not increasing activity. Conversely, during the reset test, when humans report no pain during both the intertrial offset and the initial contacts of the second train of stimuli (followed by another period of augmenting pain), most WDR lamina V cells show maintained activity, and all WDR lamina V cells again show an immediate plateau response without a period of quiescence during the initial contacts and without a subsequent augmentation. This lack of correspondence is consistent with the inability of WDR lamina V STT cells to explain the burning pain caused by the thermal grill illusion (Craig and Bushnell 1994) or by cooling during a peripheral nerve block of A-fiber conduction (because such innocuous thermal stimuli do not activate them: Willis and Westlund 1998; confirmed in this laboratory).
These data rectify an oft-cited claim that lamina V WDR cells display an incrementing (wind-up) response to repeated heat pulses (Price et al. 1978). That study used only three stimuli, and in fact, showed an increment with the second stimulus, but not the third, which is consistent with the plateau response observed in the present experiments. A subsequent study from the same laboratory that compared NS and WDR trigeminothalamic cells in the awake monkey also concluded that WDR cells "encode" heat pain, based on stimulus-response slopes to noxious heat and correlations with behavioral responses (Dubner et al. 1989; Maixner et al. 1989). However, the histology illustrated in that report indicated that most of the recording sites were in lamina I, and so their "WDR" cells may have actually been miscategorized HPC cells (which had not been recognized yet), because thermoneutral probes were not compared with room temperature (i.e., cold) probes during unit characterization (see Craig 2003). Furthermore, an earlier comparison of pain elicited in human patients by two-pulse stimulation in the C1-2 anterolateral quadrant with the refractory periods of monkey STT axons also concluded that activation of WDR lamina V axons caused burning pain (Mayer et al. 1975). However, those psychophysical observations are similarly more readily explained by activation of the previously unrecognized HPC lamina I STT axons (Craig 2003), and a direct examination of the refractory periods of their axons at C1-2 would be appropriate.
Therefore the present results, indicating that lamina I, but not lamina V, STT activity corresponds with burning pain, contradict the conventional pattern/intensity view that WDR lamina V cells are essential for all types of pain sensation, a view which has been questioned on numerous grounds (Craig 2003; Perl 1984). The present findings, however, do not discount the possibility that subpopulations of WDR lamina V STT cells may have some role in the overall experience of pain, perhaps by contributing to the intensity of sharp (first) pain (see Andrew and Craig 2002) or by inducing arousal or by dysfunctional integration under neuropathic conditions.
On the other hand, the present observations are entirely consistent with the alternative possibility that lamina V cells subserve sensorimotor integration (Oscarsson 1973; Lundberg et al. 1987). In the present study, almost all WDR lamina V STT neurons displayed clear proprioceptive sensitivity to limb position (Fig. 3); apparently, this was not reported by prior studies because the hindlimb was fixed in place (Price et al. 2003; cf. Milne et al. 1982; Willis and Westlund 1998). Certainly, innocuous limb movements and changes in limb position are not normally associated with any type of pain. A role in sensorimotor integration is also supported by recent evidence that lamina V cells are musculotopically organized, have excitatory and inhibitory receptive fields on opposing limb surfaces, and are intercalated in the flexor reflex arc (McGaraughty and Henry 1997; Schouenborg et al. 1995). Their other major projections (ventral horn, inferior olive, and cerebellum) are similarly involved in sensorimotor integration and the control of skeletal musculature.
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GRANTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. D. Craig, Atkinson Research Lab., Barrow Neurological Inst., 350 West Thomas Rd., Phoenix, AZ 85013 (E-mail: bcraig{at}chw.edu).
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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