Mechanisms of Below-Level Pain Following Spinal Cord Injury (SCI)

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Mechanisms of below-level pain following spinal cord injury (SCI) Chuck Vierck Ph.D. PII: DOI: Reference:

S1526-5900(19)30789-8 https://doi.org/10.1016/j.jpain.2019.08.007 YJPAI 3781

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Journal of Pain

Received date: Revised date: Accepted date:

15 February 2019 5 July 2019 7 August 2019

Please cite this article as: Chuck Vierck Ph.D. , Mechanisms of below-level pain following spinal cord injury (SCI), Journal of Pain (2019), doi: https://doi.org/10.1016/j.jpain.2019.08.007

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Highlights     

Nociceptive processing below spinal transections often is equated with SCI pain But pain sensations depend on cerebral cortical processing Also, most cases of below-level SCI pain are incomplete spinal injuries Therefore, effects of restricted spinal lesions on cerebral pain encoding are reviewed Human and lab animal studies agree on the effects and suggest therapies for SCI pain

Mechanisms of below-level pain following spinal cord injury (SCI) Chuck Vierck, Ph.D. University of Florida College of Medicine and McKnight Brain Institute Gainesville, Fl, 32160-0244 Corresponding author: C. J. Vierck, Ph.D. Department of Neuroscience University of Florida College of Medicine Gainesville, FL 32160-0244 Email: [email protected] Telephone: 352 275-4123

Key words: Spinal cord injury; Below-level pain; Central pain; Spinothalamic cordotomy; Deafferentation pain Running title: Below-level SCI pain Disclosures: Research Funding: No funding sources were provided for this review. Conflicts of interest: No conflicts exist

Abstract Mechanisms of below-level pain are discoverable as rostral neural adaptations to spinal injury. Accordingly, the strategy of investigations summarized here has been to characterize behavioral and neural responses to below-level stimulation over time following selective lesions of spinal gray and/or white matter. Assessments of human pain and the pain sensitivity of humans and laboratory animals following spinal injury have revealed common disruptions of pain processing. Interruption of the spinothalamic pathway partially deafferents nocireceptive cerebral neurons, rendering them spontaneously active and hypersensitive to remaining inputs. The spontaneous activity among these neurons is disorganized and unlikely to generate pain. However, activation of these neurons by their remaining inputs can result in chronic pain. Also, injury to spinal gray matter results in a cascade of secondary events, including excitotoxicity, with rostral propagation of excitatory influences that contribute to activation of deafferented neurons and chronic pain. Establishment and maintenance of below-level pain results from combined influences of injured and spared axons in the spinal white matter and injured neurons in spinal gray matter on processing of nociception by hyperexcitable cerebral neurons that are partially deafferented. A model of spinal stenosis suggests that ischemic injury to the core spinal region can generate below-level pain. Additional questions are raised about demyelination, epileptic discharge, autonomic activation, prolonged activity of C nocireceptive neurons and thalamocortical plasticity in the generation of below-level pain. Perspective An understanding of mechanisms can direct therapeutic approaches to prevent development of below-level pain or arrest it following SCI. Among the possibilities covered here are surgical and other means of attenuating gray matter excitotoxicity and ascending propagation of excitatory influences from spinal lesions to thalamocortical systems involved in pain encoding and arousal. 1. Introduction Traumatic/contusive spinal injury produces all or most of the following disruptions of spinal cord integrity: tearing of the meninges with leakage of cerebral spinal fluid (CSF); disruption of the blood–spinal cord barrier; vertebral scarring with eventual tethering/compression of the cord;

inflammation; vascular disruption with hemorrhage, edema and ischemia; free-radical injury with neuronal excitotoxicity, at-level neuronal hyperactivity, apoptosis and eventual cellular loss; mitochondrial dysfunction; electrolytic changes; accumulation or loss of transmitters; up- and downregulation of transmitter receptors; damage to and/or constriction of dorsal and ventral roots; demyelination of propriospinal and long-track axons; interruption of long ascending and descending pathways to an indeterminant extent, with anterograde and retrograde degeneration; gliosis and scarring with impaired regeneration of axons; and spontaneous activity rostral and caudal to the injury in proportion to the extent and duration of neuronal deafferentation (70;94;137). Until recently, the above-listed disruptions of spinal integrity have been regarded either as contributors to gray matter damage, with at-level influences, including pain, or as contributors to white matter damage, with below-level sensory or motor influences. The motor effects are readily understood in terms of interrupted descending axons, with loss of conscious movement and disruption of reflexes, including limb flexion/withdrawal. Below-level sensory effects are less readily understood in terms of interrupted ascending axons. For example, pain can be referred to the L3 dermatome following SCI at T5. Neuronal abnormalities at L3 do not explain the pain when transmission to the brain from L3 is interrupted at T5. This review is concerned with mechanisms of altered cerebral processing that results in referral of pain to spinal segments below SCI. Traumatic SCI has been modeled in laboratory animals by applying static or dynamic pressure to an exposed spinal cord, producing contusive injury to the core region of gray and white matter, often with cystic cavitation and preservation of a variable rim of white matter (45;49;96;159). This procedure has helped to define the limits of motor recovery from SCI (9) and to evaluate therapeutic approaches to below-level paralysis (42;87). However, no two traumatic/contusive spinal lesions are alike in terms of the disruptions listed above. In particular, relating the presence and characteristics of below-level pain to spinal lesion configurations – a logical first approach to understanding mechanisms – is not a reasonable goal for traumatic/contusive injuries. Below-level SCI pain develops slowly, over months to years for some individuals and not others. Therefore, an appropriate laboratory animal model of SCI pain should detect post-injury changes in pain sensitivity with an incidence and time-course similar to the development of below-level pain of humans following SCI. However, sensitivity to below-level stimulation can be assessed only when some nociceptive conduction to thalamic and cortical levels is spared by SCI. Therefore, this review presents operant escape performance during nociceptive stimulation within dermatomes below selective

(incomplete) lesions of the spinal gray and/or white matter of laboratory animals. These behavioral tests more directly assess the aversive impact of pain sensations than recordings or images of neuronal activity. However¸ changes in operant pain sensitivities of monkeys and rats can be validated by recordings and images plus observations of chronic pain and the pain sensitivity of humans following similar spinal lesions. 2. Background and methodological considerations 2A. Spontaneous behaviors Evaluation of pain in laboratory animals often has been misdirected and misleading. One approach has linked persistent licking/biting at a site on a lower limb or tail (self- injurious behavior: SIB) with ongoing pain (114). However, evidence against attributing specific sensations to SIB has been presented by tetraplegic individuals with ASIA type A (clinically complete) SCI (60). SIB of the fingers of 5 patients fits the common pattern of distal extremity damage observed in laboratory animals following nerve or spinal injury. However, the hands were insensate for stimulation of all five patients, and SCI pain was absent (3 patients) or was localized to the abdomen and pelvis rather than the fingers (2 patients). Thus, SIB for these individuals was permitted by a loss of digital sensation but was not elicited in response to chronic pain at the location of injury. SIB could occur as a reaction to any unusual and unwanted sensation such as numbness, itch or paresthesia. Another unverifiable interpretation is that an animal without an understanding of causation attacks an anesthetic limb because it is insensate and viewed as not belonging to the animal. Thus, laboratory animal evidence for the possibility that spontaneous behaviors result from an abnormal sensation that could be pain requires somatotopically appropriate recordings or images of abnormal activity within nociceptive pathways only during episodes of SIB. And the neural activity must not be elicited by the behavior. 2B. Innate behavioral reactions to chronic pain or nociceptive stimulation Simple observation of ongoing behaviors like those which can occur in response to nociceptive stimulation has been presumed to indicate the presence of chronic pain. However, chronic pain seldom elicits behaviors that can be observed in reaction to acute pain. For example, patients can describe ongoing SCI pain in detail without overt behavioral evidence of what they are experiencing (218). Also, claims that pain is associated with a motor action should not be made without determining that the

behavior reflects properties of the pain such as timing and intensity (see section 2C, below). This is not possible with chronic pain of laboratory animals, because its presence is hypothetical, and its intensity is unknown. Opioid administration has been utilized by laboratory animal researchers to identify innate behaviors that are sensitive to modulation of pain (48). For example, a reduced frequency of vocalizations after administration of an opioid could indicate attenuation of pain resulting from experimentally induced arthritis (99). Similarly, vocalizations by monkeys in response to electrocutaneous stimulation are substantially reduced by a low dose of morphine (0.25 mg/kg), which reduces activity levels and second pain (25;26;27;223). However, first pain during electrocutaneous stimulation is not attenuated by low-dose morphine (25). Furthermore, vocalizations and activity levels of monkeys while performing for food reinforcement, without nociceptive stimulation, are reduced by low dose morphine (26). Opioid induced silence and inactivity are adaptive for an animal recovering in the wild from injury, but these can be direct effects of morphine that are not representative of analgesia. Frequently, the dosage of morphine is increased until an innate behavior is suppressed, and this effect is considered to be analgesia. However, opioids affect a variety of motoric actions, inhibiting or enhancing innate behaviors, as dictated by dosage (23). Some of these effects, on non-nociceptive as well as nociceptive reflexes, have been shown to result from occupancy of mu opioid receptors on spinal motoneurons by DAMGO (86;164). Furthermore, high doses of morphine (e.g., 10 mg/kg) produce hyperactivity, which masquerades as antinociception in assays of locomotor slowing by assumed pain (e.g., (84)). Reflexive reactions to stimulation do not provide valid assessments of any modality of sensory perception by humans. And yet, flexion/withdrawal reflexes have been the preferred behaviors for evaluation of laboratory animal pain (88). This approach has been utilized in SCI research, even though SCI can eliminate below-level somatosensation (2;98;132) but produces the spastic syndrome (flexor spasms with enhanced reflexes) (13;37;153). The spastic syndrome and chronic, below-level pain each can exist without the other following SCI, because of separate mechanistic determinations. Limb or tail flexion/withdrawal reflexes can terminate a nociceptive stimulus, but these responses of the stimulated limb are not consciously mediated and therefore do not provide a test of pain sensitivity. Sensory transmission to motoneurons for flexion\withdrawal can be disynaptic, and it

precedes and is independent of conscious escape (188;193). Therefore, enhancement of below-level flexion/withdrawal of a limb following SCI is not evidence that pain has been increased. There could be episodes of spontaneous activity among flexor motoneurons that have lost corticospinal input. Or, flexion/withdrawal reflexes can be released by interruption of descending inhibition that is directed to reflex circuits, excluding spinothalamic projection cells. Basically, below-level pain cannot be revealed by the activity of spinal neurons, without knowing whether and how the activity of those neurons is processed rostrally. Pain does not exist at the spinal level; it necessarily results from interactions between nocireceptive thalamic and cortical neurons. Also, behavioral evaluation of SCI pain must involve cortically mediated, conscious responses to painful, but not to painless stimuli. 2C. Operant testing of sensitivity to painful electrocutaneous stimulation Learned operant escape from nociceptive stimulation requires: transmission of hindlimb nociception to cortical levels for pain processing (including attention and intensity assessment), followed by a decision whether or not to terminate stimulation, directed by memories of available options, and then execution of a response that is adapted to the environment. These requirements determine that the response is consciously mediated and therefore can be validated by human observers who consciously evaluate sensations evoked by similar stimuli. Learned escape from electrocutaneous stimulation of either foot (hooded rats) or lateral calf (Macaque monkeys) reveals essential characteristics of operant pain sensitivity (186;189;193). The animals are loosely restrained in a sling (rats) or primate chair, with a manipulandum positioned near one forepaw or hand for escape responding. Forelimb responses with latencies greater than 150 msec. are recorded as escapes. Both hindpaws or feet of rats and monkeys are tethered to force transducers so that hindlimb flexion responses can be monitored. Correspondence of human pain ratings and laboratory animals’ operant responses is critical to validation of monkeys’ or rats’ behavior as indicants of normal and abnormal somatosensation. For example, in an experiment designed to determine detection thresholds for electrocutaneous stimulation, monkeys were trained to pull a lever for liquid reinforcement when they felt a sensation (71). This operant task determined the stimulus intensity associated with detection of electrocutaneous stimulation (50% hits), which ranged from 0.005 to 0.01 mA/mm2 (expressed as current density). Human subjects have rated non-painful sensations evoked by electrocutaneous stimulation of the lateral calf as detectable at 0.01 mA/mm2 .

For operant escape testing of monkeys, food reinforcement is not present, so that motivation for bar pulls is restricted to termination of electrocutaneous stimulation. The presence or absence of pain is revealed by escape frequency as a function of stimulus intensity. Thresholds for escape (50% responding) by monkeys averaged 0.7 mA/mm2, and human thresholds for pain averaged 0.5 mA/mm2 (187). Thus, escape by normal monkeys from intensities of 0.7 mA/mm2 and above can be regarded as conscious terminations of pain. Human ratings of pain and escape responding of rats can be compared for electrocutaneous stimulation dorsoventrally across a little finger (humans) or foot (rats). Human thresholds for finger pain are 0.7 mA/mm2; thresholds for a pulsatile, sharp sensation average 0.4 mA/mm2; and thresholds for itch average 0.1 mA/mm2 (193). The rats consistently escape electrocutaneous stimulation of 0.4 mA/mm2, which is described by human subjects as startling but not painful. Thus, conservative interpretation of the rats’ behavior attributes escapes of 0.7 mA/mm2 and higher to terminations of pain. Stimulus-response

(SR) functions define relationships between stimulus intensities and

suprathreshold pain intensities, which can be critical for detecting abnormal pain sensitivity (e.g., hyperalgesia or hyperpathia). Magnitude estimation is a preferred method for establishing SR functions of human pain intensity (199). Visual analog scaling (VAS) often is utilized in human studies of pain magnitude, constraining ratings between 0, which denotes no pain, and 100, which represents intolerable pain. Alternatively, a method of free (unconstrained) magnitude estimation asks that subjects respond to stimulation by generating force (e.g., squeezing an ergometer) in proportion to the magnitude of pain. Free magnitude estimation has been adapted for laboratory animals by placing a force transducer in series with a response manipulandum so that the force of operant escape responses is recorded and stored (188). Higher intensities of pain demand urgency, naturally dictating short latencies and high forces. When human and three species of monkey subjects terminated electrocutaneous stimulation by pulling on a manipulandum, escape forces increased and latencies decreased for stimulation intensities from 0.5 to 2.5 mA/mm2 (187). Thus, the available measures of operant escape in monkeys and rats closely approximate the pain sensitivity of human subjects to the same ranges of nociceptive electrical stimulation.

3. Effects of anterolateral spinal injury on flexion/withdrawal and operant escape from electrocutaneous stimulation In direct comparisons, flexion/withdrawal and conscious escape responses of laboratory animals are not affected equivalently by a variety of experimental manipulations (180;181;183;188;191;192;194;200;201;202;203). For the purposes of this review, effects of ascending spinothalamic axonal interruption on clinical pain and pain sensitivity are critically important. In contrast to the strictly contralateral and below-level reduction of pain sensitivity after anterolateral cordotomy of monkeys, rats and humans (71;102;193) a bilateral, below-level reduction in the amplitude of hindlimb withdrawal responses is observed following unilateral section of the spinothalamic tract (71;183;188;193;194). Following cordotomy, escape testing reveals sensory consequences of ascending spinothalamic interruption, and flexion/withdrawal responses reveal motor consequences of descending axonal interruption. The effects of anterolateral cordotomy on pain sensations and flexion reflexes of humans are similarly dissociated (62). Unilateral interruption of the spinothalamic tract partially deafferents nocireceptive thalamic and cortical neurons with below-level and contralateral receptive fields. Thalamic and cortical neurons can be inactivated initially following deafferentation (15), consistent with hypoalgesia following cordotomy. However, relationships over time in the sensitivity of partially deafferented nocireceptive neurons and operant pain sensitivity are unknown, needing investigation in awake and behaving animals. 4. Increased pain sensitivity over time after cordotomy – a model of below-level SCI pain Escape performance of 15 Macaca nemistrina monkeys was as expected after anterolateral cordotomy -- a contralateral increase in escape latency (hypoalgesia) (71;188). Early postoperative escape from electrocutaneous stimulation of the ipsilateral leg was near or identical to preoperative performance. However, the contralateral escape responding of 7 of the 15 animals increased substantially over the course of postoperative testing (up to 21 months), returning to preoperative levels of pain sensitivity or beyond at an average of 27 weeks post-surgery. This effect mimics the postcordotomy recovery of contralateral pain sensitivity by some patients with cancer pain (213), but there was no peripheral source of pain for the monkeys. Therefore, the source of increased contralateral pain sensitivity for the monkeys was central.

Other features of the escape performance of monkeys following cordotomy are of interest: 1) Cordotomy produces a contralateral hypoalgesia, but not analgesia, in the early postoperative period, consistent with human cordotomy (102). 2) The increase in pain sensitivity over time following cordotomy was bilateral. Development of ipsilateral hyperalgesia was observed for all 7 animals with recovered contralateral pain sensitivity. This result fits with reports of mirror image (ipsilateral) pain following unilateral human cordotomy (18). 5. Spinal gray and white matter injury A common assumption that SCI effects on below-level pain can be attributed entirely to interruption of spinothalamic or other white matter axons may not be correct. Comparison of spinal lesions revealed more gray matter damage for monkeys with contralateral recovery of pain sensitivity, compared to 8 monkeys that did not recover from contralateral hypoalgesia over one year of postcordotomy testing. Hence, a hypothesis that spinal gray matter damage can contribute to development of hyperalgesia following cordotomy. Subsequent to studies of primate cordotomy, we turned to a rat model with and without abnormal gray matter activation (194). A pledget of Gelfoam, soaked in the animal’s blood, was introduced into the lesion cavity of some animals. Hemoglobin, an epileptogenic agent (217), clearly altered postoperative escape performance. Ipsilateral hyperalgesia was observed consistently over 76 postoperative test sessions (20 weeks), compared to cordotomy without Gelfoam and blood. This contribution of gray matter injury is consistent with a human case study of chronic pain and hypersensitivity associated with spinal cavernous hemangioma (67). Also, an fMRI evaluation of the spinal lesions of SCI patients showed a relationship between gray matter injury and below-level pain (52). 6. Spinal gray matter injury Traumatic damage to spinal gray matter results in neuronal excitotoxicity, abnormal discharge, and enhanced responses to input for neurons within and surrounding the injured segment (40;79;107;109;194). These effects combine with white matter damage to elevate below-level pain sensitivity, raising questions concerning long-range effects of lesions confined to gray matter. At-level neuronal hyperactivity of spinal neurons that have sustained damage is related to upregulation of sodium channel Nav1.3 (209). Also, effects of gray matter excitotoxicity, with minimal or no contributions of white matter injury, have been modeled by injection of the AMPA-metabotropic receptor agonist quisqualic acid (QUIS) into spinal gray matter. Abnormal spontaneous discharge of at-

level neurons, hypersensitivity to segmental input, and SIB of segments bordering the injection, are observed (14;224;225;226). An investigation of caudal influences of QUIS injections into thoracic gray matter evaluated sacrocaudal reflex modulation via the propriospinal system of intersegmental connections (204). Staggered left and right hemisections (1-2 segments apart) were placed between lumbar segments with input from the hindlimbs and sacrocaudal segments with input from the tail tip. The intent was to transect long spinal pathways but spare short propriospinal connections between hindlimb and tail segments. QUIS injections were then placed in the thoracic gray matter. The amplitude and duration of reflex tail responses to a single pulse were increased relative to post-hemisection / pre-QUIS responses. These results show that abnormal gray matter activity can be propagated diffusely over the propriospinal system of short, intersegmental projections, exerting excitatory influences. In a test of rostral influences of gray matter injury, QUIS injections into the gray matter of rats at T12-L3 preceded imaging of cerebral cortical activity (128). Three to 6 weeks following excitotoxic damage to the T12-L3 spinal gray matter, cerebral blood flow (rCBF) in thalamic nucleus ventralis posterolateralis (VPL) and the primary somatosensory cortex (SI) was increased relative to animals without prior QUIS injections. Excitatory influences emanated rostrally from the focal gray matter injury, activating somatosensory thalamic and cortical neurons. Consistent with this result, excitotoxic injury to thoracic gray matter produces hyperalgesia for operant escape from thermal stimulation of the hindpaws (1). 7. Gray matter damage from spinal stenosis Typically, traumatic SCI narrows the spinal canal, compressing the spinal cord and producing a condition of stenosis. Blood flow to the spinal gray matter is compromised, with ischemic damage and eventual development of a cystic cavity in some cases (4;145). Seeking to evaluate effects of spinal compression on pain sensitivity, female rats underwent a surgical procedure with subdural insertion of a polymer (Hydrotite) that expands over time with hydration (182). Pre- and postoperative pain testing involved thermal stimulation from a preheated floor in a dark compartment, with the option to occupy a brightly lit compartment. Opposing aversions for bright light and thermal pain motivated the animals to cycle back and forth between the two compartments. The proportion of 15 min. trials spent in the brightly lit compartment evaluates aversion to (escape from) thermal stimulation. Compared to presurgical tests, escape durations from 10oC and 44.5oC gradually increased over 30

weeks, revealing cold and heat hyperalgesia following polymer implantation at T10-12. Subsequent removal of the polymer from 5 animals returned heat sensitivity to normal preoperative values, but cold sensitivity remained elevated. Standard histology at the completion of behavioral testing revealed cystic cavities in the spinal cords of 6 animals, consistent with a high probability of cyst formation if stenosis from spinal fracture is not reduced (145). However, the cords of 10 animals were distorted without evidence of cysts. Taking advantage of repeated measures over months of testing, a statistical estimate of postoperative thermal sensitivity was calculated for individual animals: 8 of 10 animals without cysts were significantly hyperalgesic. Thus, delayed, below-level hyperalgesia occurred in cases without evidence of white matter damage at the site of compression. Demyelination is a predictable consequence of traumatic SCI with stenosis (66;101;137;139;141;177), and demyelinated axons discharge action potentials spontaneously (35;120;129;222). Therefore, effects of Gabapentin were evaluated for animals with stable hyperalgesia following stenosis. Beginning 45 min. after 100 mg/kg Gabapentin administration, escape from 10oC and 44.5oC was reduced, compared to vehicle injection. This finding is consistent with the possibility that demyelination of ascending axons is a factor in development of below-level SCI pain (56;134). 8. Inflammation, demyelination and SCI pain When inflammation accompanies traumatic or compressive SCI (42;163;206;231), its role in development of chronic pain is confounded with other mechanisms. However, spinal myelitis pain can evolve from isolated inflammation within the spinal gray matter (8;19;97;116;124;125;148;167;230). For example, neuromyelitis optica involves destruction of astrocytes, disruption of the blood-spinal cord barrier and infiltration of inflammatory agents into the spinal gray matter. Eventually, degeneration of oligodendroglia and demyelination are present at dermatomal levels beyond the original distribution of spinal damage. Thus, demyelinated axons associated with SCI represents a significant risk factor for below-level pain. Similarly, the pain of multiple sclerosis (MS) can involve patches of demyelinated axons in the lateral spinal column (17;148). 9. Prolonged activation of C nocireceptive neurons The sensations elicited by prolonged or repetitive activation of C nociceptive projection systems are fundamentally different from comparable stimulation of myelinated afferents. Repetitive

stimulation of myelinated afferents (either non-painful tactile or A-delta nociceptive) leads to sensory suppression by adaptation (69;155) or habituation (65) or inhibition (108). However, repetitive stimulation of C nociceptors summates (121;184;196), and prolonged activation of C nociceptors by thermal stimulation is associated with hyperalgesia, rather than adaptation (196). Cortical area 3a neurons are activated for hours following C nociceptor stimulation by intracutaneous capsaicin injection (214). Accordingly, rostral transmission from C nocireceptive neurons that are abnormally activated within the gray matter of a spinal lesion likely produces severe pain. Also, chronic pain from activation of C nociceptive projection systems is likely refractive to opioid suppression. Opioid agents strongly suppress acute pain from activation of C nociceptors (27;180;223), but they are not effective, long term, for control of neuropathic or SCI pain (78;219;220). Possibly, mammalian central nervous systems are not designed to (have not evolved mechanisms to) suppress chronic pain. 10. Ablation of spinothalamic projection cells in the superficial dorsal horn Prolonged C nociceptor input to spinal lamina 1 cells is implicated as a cause of the most troubling forms of chronic pain (166;212).

Therefore, intrathecal administration of a neurotoxin that

ablates spinothalamic projection cells in the superficial dorsal horn provides an option for control of chronic SCI pain. Substance P is released by unmyelinated (C) nociceptor terminals in the superficial dorsal horn (39), synapsing on and exciting spinothalamic projection neurons containing the substance P receptor NK-IR (227). Following intrathecal injection of a neurotoxic agent (substance P–saporin: SP-sap or SSPsap) internalization of substance P by NK-1R receptors in response to nociceptive stimulation ablates spinothalamic neurons in the superficial dorsal horn (150). This procedure eliminates a population of neurons that project C nociceptor input from spinal lamina 1 to the posterior group of thalamic nuclei and then to area 3a of SI (198). Spinothalamic projection from the deep dorsal horn to thalamic nucleus ventralis posterolateralis (VPL) and then areas 3b and 1 of the primary somatosensory cortex (SI) is spared (29). Intrathecal administration of SP-sap or SSP-sap into the lumbosacral CSF reduces thermal pain sensitivity of rats, using the method of assessing relative aversions for bright light and thermal stimulation (191). Escape from 0.3oC, 44oC and 47oC is significantly reduced (192;215). A 58% loss of NK-1R receptor staining in lumbosacral laminae I and II attenuates operant responses to thermal pain for at least 4 months. Also, a test of sensitized responding to 44oC provides evidence for a loss of pain

from activation of C nociceptors. Three hours following application of mustard oil to the hindpaws, escape from 44oC is substantially increased, prior to but not after intrathecal injection of SP- or SSP-sap (192;215). Lick/guard reflex responding to 0.3oC, 44oC and 47oC is not affected by intrathecal SP- or SSPsap, with or without prior application of mustard oil (192;215). 11. Surgical attenuation of abnormal output from the spinal gray matter A surgical approach to at-level chronic pain following SCI involves coagulation of the superficial dorsal horn throughout the injured spinal segments (dorsal root entry zone lesions: DREZ) (169). The intent of this procedure is to ablate at-level spinal neurons that are spontaneously active and hypersensitive to inputs (152). A refinement of DREZ surgery involves guidance of lesion placement with recordings of spontaneous neuronal hyperactivity and of evoked responses to transcutaneous stimulation of C nociceptors (46). With electrophysiological guidance, aberrant activity in and transmission from the superficial dorsal horn can be eliminated by DREZ surgery. Although intended to control at-level pain (161), guided DREZ microcoagulation also affects below-level pain. Among a cohort of 26 patients, 81% reported 100% relief of below-level pain following at-level DREZ surgery (46). This finding shows that hyperactivity of C nocireceptive neurons at the level of SCI can be a determining factor in below-level pain. Other issues concerning mechanisms of below-level pain following complete SCI have been addressed by guided DREZ surgery below complete SCI (47): 1) Recordings revealed patches of hyperactive neurons in the superficial dorsal horn, below-level. Ablation of these neurons eliminated chronic pain that was referred to the spinal segments with hyperactive neurons (47). Thus, the superficial dorsal horn can be susceptible to injury at segments remote from a major spinal infarct. When the patches of hyperactive neurons are below-level, the pain is below-level, but it is at-level with reference to the patches. 2) These patients had not benefitted from cordectomy, insuring complete spinal injuries. The authors attribute the efficacy of below-level DREZ surgery to elimination of transmission of abnormal activity from the injured spinal patches to the sympathetic nervous system. 12. Gray matter injury and sympathetic activation In addition to transmission of excitatory influences rostrally and caudally from SCI, neurons in thoracic and lumbar segments communicate with the sympathetic nervous system via rostral projections from lamina X neurons and from connections between the intermediolateral column and the sympathetic chain of the autonomic nervous system. Accordingly, below-level sensory stimulation

of patients with thoracic spinal injuries can generate autonomic dysreflexia. The sympathetic nervous system of these patients is abnormally activated, as revealed by episodes of severe hypertension (123). Laboratory animal evidence that excitotoxic injury within the thoracic gray matter can influence the sympathetic nervous system has been provided by evaluating effects of QUIS injections on autonomic activation by psychological stress (190). Female rats could occupy either a compartment with a floor temperature of 45oC or an adjacent compartment with the floor temperature set to 15oC. Before QUIS injection, aversion for cold (more time on the 45oC plate) converted to a relative aversion to heat (a preference for the cold plate) at 30 min. following restraint stress. The cold aversion returned at 24 hours after restraint. Thermal preferences then were evaluated after injection of QUIS at spinal segments ranging from T8 to L3. Post-QUIS injection, an aversion to heat was present in the absence of stress, and heat aversion was enhanced further at 30 min. and 24 hours following restraint stress. Thus, excitotoxic injury to thoracic gray matter influenced autonomic temperature regulation, increasing aversion to nociceptive heat and enhancing the amount and duration of autonomic activation by restraint stress. Sympathetic activation by psychological stress is implicated in the genesis of chronic musculoskeletal pain (126;178;179), which can trigger below-level SCI pain. 13. Combined interruption of spinothalamic and medial lemniscal pathways. Inhibitory modulation of pain intensity can occur via inputs to the thalamus and cortex from lemniscal and spinothalamic pathways (214). Accordingly, the magnitude of chronic, below-level pain is increased for SCI patients when both spinothalamic and medial lemniscal sensitivities are lost (31). GABA expression in VPL is depleted by dorsal column injury (150;151) and by combined lemniscal and spinothalamic lesions (149). Also, thalamic levels of GABA are reduced for individuals with traumatic SCI and below-level neuropathic pain (76). Blood flow for these individuals is reduced in the thalamic reticular nucleus -- an important source of thalamic GABA modulation (36;72;146). 14. The minimal spinal lesion resulting in contralateral analgesia Understanding recovery over time from a contralateral reduction in pain sensitivity following cordotomy requires identification of the spinal pathway(s) that support pain sensitivity following interruption of the lateral spinothalamic tract. Cebus albifrons monkeys were tested for operant escape from activation of myelinated nociceptors by electrocutaneous stimulation (195). Following cordotomy on the left, pain sensitivity decreased and then recovered on the right. Secondary lesions of four animals included the left anterolateral and ventral columns, or the spinal cord was hemisected on the

left. Following the second lesions, these animals recovered from reduced pain sensitivity on the right. Therefore, contralateral recovery from cordotomy is not a result of incomplete interruption of the spinothalamic tract on one side. Following recovery from a primary lesion of the anterior and anterolateral columns on the left, interruption of the anterolateral column on the right produced only a transient, bilateral reduction of pain sensitivity. Thus, bilateral interruption of the spinothalamic pathway did not produce analgesia for these animals. However, complete ventral hemisection produced a bilateral loss of pain sensitivity that recovered only marginally over 42 weeks of escape testing. Thus, below-level analgesia depends upon bilateral interruption of spinothalamic, spinoreticular and propriospinal axons in the anterolateral and anterior columns (33). Implications of these findings are: 1) Rostral nociceptive conduction via pathways other than spinothalamic supports sensations of pain. 2) Because chronic pain develops following chordotomy but not after ventral hemisection, chronic pain/hyperalgesia must depend upon spinothalamic interruption and sparing of other anterior/anterolateral pathways – likely spinoreticular (32;63;140). 15. What are the sufficient conditions for development of below-level pain? Investigators have wondered whether spinothalamic injury is sufficient for development of hyperalgesia and chronic SCI pain (41;54;80;205;207). In addition to the possibility that some spinoreticular sparing is important, neuronal excitability/hyperactivity, at-level, appears to be necessary for development of below-level pain (52;56). If so, at-level pain should precede or coincide with development of below-level pain. Prospective observations of 73 SCI patients (158) has noted that the percentage of at-level pain decreased, and below-level pain increased, from 3 months to 5 years post-injury, and nearly identical numbers of patients reported both at- and below-level pain at 5 years. Another investigation of 15 patients with thoracic SCI has demonstrated at-level hypersensitivity for 8 patients (205). Six of these reported below-level pain. In contrast, 7 patients without at-level hypersensitivity did not report below-level pain. Thus, at-level pain can precede development of below-level pain, but prospective information on individual patients is needed. The conditions that foster development of below-level pain could explain why it does not occur in some cases. The relative amounts of spinothalamic vs. spinoreticular damage may not be optimal for below-level pain development. Also, minimal activity within (and from) the spinal gray matter might not support development of below-level pain.

16. Complete, incomplete and discomplete SCI Often, some neural transmission occurs past a spinal injury judged to be clinically complete by standardized neurological testing (ASIA A) of motor control, pinprick and touch sensitivity below-level. These spinal lesions are termed discomplete (7;51;157). Discomplete sparing is difficult to document but is crucial for understanding different categories of SCI pain and their mechanisms and appropriate therapies. Evaluation of fMRI responses to below-level, repetitive tactile stimulation of 48% of 23 clinically complete SCI patients revealed activity in the contralateral thalamus, SI, and S2 (221). In another study, 19 of 24 ASIA A patients (79%) reported sensations elicited by stimulation below-level with pressure, cold, heat, skinfold pinch or repetitive pinprick (51). Generally, the duration of stimulation must be long, and the elicited sensations are not specific to the stimulus modality but are described as tingling, unpleasant, nonspecific or diffuse. Histological or fMRI evaluations of spinal injuries have shown that a rim of intact axons can be present in 58-62% of clinically complete (ASIA A) injuries (20;51;94;95). In the anterior/anterolateral white matter, these include spinoreticular and propriospinal axons that originate predominantly in deep laminae of the spinal gray matter and outnumber spinothalamic axons. All somatosensory and visceral modalities converge onto spinoreticular cells (6;57;77;100;122), with multisynaptic projection up the neuraxis. Rostral conduction is slow (33), impairing detection of activation by averaged evoked potential recording (63;118). Receptive fields often are large and bilateral. Somatotopic localization and receptor specificity are not served by this system, but nociception is well represented. Below-level pain following complete spinal transection by traumatic SCI may be rare. Any axons that are spared by SCI can be undetected by standard means, and yet they can activate partially deafferented thalamic and cortical cells. For example, 8 of 12 individuals with clinically complete SCI and below-level chronic pain received thermal stimulation following sensitization of C nociceptive afferents by below-level cutaneous application of capsaicin. The thermal stimulation triggered sensations matching the patients’ clinical pain. However, individuals without below-level pain did not perceive pain following application of capsaicin and then thermal stimulation. According to the authors, this result indicates that “…activity in uninjured fibers contributes to neuropathic pain…”. However, axons spared by SCI could be injured.

Axons which survive transection by SCI become exposed to conditions which, over time, generate abnormal activity that is propagated rostrally (168). Activation of microglia in a region of injury damages oligodendrocytes and demyelinates axons (12). Demyelinated nociceptive axons can become hyperactive and generate pain (35;129). Also, when microglia are activated by SCI, they release a variety of pro-inflammatory factors (16;147). Accordingly, neuronal hyperactivity after contusive spinal injury is reduced following administration of minocycline (a microglial inhibitor) (168).

17. Epileptic activity and chronic pain Epileptic activity among nociceptive neurons can result in chronic pain, but how is it generated by SCI? A model of epileptic generation involves knife cuts of the corona radiata of cats, severing thalamic inputs to a population of cortical neurons (176). EEG recordings from these cortical slices progress in minutes from depressed slow waves to recovery (normal EEG amplitudes and patterns) and then to paroxysmal seizures (high amplitude waves with interictal spikes). However, this surely does not apply to all the neuronal assemblies deafferented by SCI. Traumatic removal of the undercut cortical slices from brains likely was responsible for the epileptiform activity. Development of epileptic activity is associated with injury to neurons and/or their processes (117). Pain following injury to a region with nociceptive neurons is exemplified by a case with trauma to the right insula (91). Propagation of seizure activity to the parietal operculum and mid cingulate gyrus resulted in pain, which was referred to the left hand or foot, progressing to the left side of the body. The pain throbbed until the spike discharge ceased. Thermocoagulation of the epileptic focus eliminated occurrences of pain attacks. Thus, traumatic injury to the spinal dorsal horn could result in rostral transmission of paroxysmal activity from nociceptive neurons (e.g., from lamina 1), resulting in at-level pain (219) and facilitating development of below-level pain. 18. Thalamic effects of SCI Contributions of spinothalamic damage to development of below-level pain is revealed by recordings from nucleus ventralis posterolateralis (VPL) of monkeys (210;211). Ipsilateral to cordotomy, rates of burst responding of multireceptive cells (MR, including nociception) to below-level, contralateral brushing are dramatically enhanced, indicative of tactile allodynia. High levels of spontaneous activity among these partially deafferented MR cells likely account for increased duration of evoked sensations. In contrast, activation of low threshold (LT) neurons ipsilateral to the lesion is not

enhanced. These results are consistent with effects on feline VPL cells following cordotomy (104) and effects on human VC cells following SCI (85;113). Thus, anterolateral cordotomy enhances the driven activity of nocireceptive thalamic cells. Below-level hypersensitivity of multireceptive (MR) cells in monkeys’ VPL declines substantially from 3 to 12 months following anterolateral cordotomy with minimal gray matter damage (211). In contrast, the substantial gray matter damage associated with traumatic SCI may be responsible for longterm maintenance of thalamic hypersensitivity. Surprisingly, MR cells with forelimb RFs are hyperactive and hypersensitive following thoracic cordotomy. Similarly thalamic (VPL) and cortical (SI) recordings from rats have revealed unmasking of neurons in the partially deafferented hindlimb regions of VPL and SI that respond to forelimb stimulation following thoracic spinal transection (3;5). This thalamic effect likely occurs in response to loss of below-level spinothalamic input to a population of spinothalamic cells at C1-3 with large and complex RFs on both forelimbs and both hindlimbs (162). The C1-3 cells comprise 40-50% of the spinal nociceptive projection to VPL (130). C1-3 spinothalamic neurons respond to forelimb stimulation with late responses to trains of strong and repetitive electrical stimulation.

19. Above-level hypersensitivity to repetitive stimulation Hypersensitivity of thalamic and cortical cells to strong and repetitive forelimb stimulation (89) is consistent with reports that patients with thoracic SCI can be hypersensitive to above-level stimulation (82;205). However, single, short duration, nociceptive stimuli do not reveal above-level allodynia/hyperalgesia following thoracic SCI (32;53;81). Thus, prolonged stimulation may be needed to reveal above-level hyperalgesia, as demonstrated by psychophysical testing of SCI patients with thoracic syrinx cavities (204;218). Temporal summation of heat pain was produced by repetitive contact of a thermode (700 msec. duration) with the thenar eminence of either hand. This method activates C nociceptors, producing late sensations that summate substantially, compared to a more common method of delivering short duration ramps that optimally activate myelinated nociceptors (43;184). Normally, 15 taps at 54oC summate from warmth to moderate pain ratings above 40/100 at an ISI of 3 sec. Subsequent 54oC stimulation at an ISI of 6 sec. does not maintain the pain ratings generated during tapping at 3 sec. ISIs and does not temporally summate. This typifies the normal, NMDA dependent windup of second heat pain (184). Responding to repetitive stimulation of the hands by 3 syringomyelia patients with sensory levels of T4, T4 and T10 differed substantially from normal: 1) Enhanced temporal summation of heat pain: Temporal summation of the patients during 3 sec. ISIs progressed to 70/100 within 15 taps at 48oC, which fails to summate normal subjects. 2) Sensitization by slow repetitive stimulation: Heat stimulation (48oC) of the patients at 6 sec. ISIs maintained and increased the high pain ratings established previously by 3 sec. ISIs. Central sensitization is not seen normally for repetitive tapping at this slow rate. 3) Dramatic enhancement of cold sensitivity: Normally, repetitive stimulation with a thermode precooled to 0.5oC produces summation of a diffuse ache sensation to a maximum intensity rating of 40 (121;204). However, the hypersensitive syringomyelia patients withdrew the stimulated hand from a sharp, cold sensation, rated at 90/100, after 3-5 contacts, demonstrating severe cold hypersensitivity. Despite hypersensitivity to repetitive heat and cold stimulation of some patients with thoracic syringomyelia, above-level chronic pain was not reported. Unfortunately, we did not ask our syringomyelia patients to describe the location and other characteristics of sensations elicited by

repetitive heat or cold stimulation of their hands. Our assumption that the pain was localized to the site of stimulation may have been incorrect. 20. Hyperpathic SCI pain The above-level sensitization of syringomyelia patients and of thalamic cells following thoracic SCI implores a hypothesis: Hyperpathic SCI pain can result from partial deafferentation and sensitization of C1-3 spinothalamic cells (subject to influences of gray matter injury and spinoreticular sparing). Explosive pain occurs in response to prolonged and strong, above-level activation of these cells following thoracic SCI. Because C1-3 spinothalamic cells respond to a variety of nociceptive inputs from all levels and both sides of the body, elicited sensations are poorly localized and difficult to identify. The IASP defines hyperpathia as: an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. Also: there can be faulty identification and localization of the stimulus, delay, radiation and an aftersensation, and the pain is often explosive. Thus, above-level nociceptive pain following thoracic SCI may be hyperpathic pain in the distribution of C1-3 spinothalamic cells. 21. Interactions between afferented and deafferented cerebral neurons following SCI of humans Neuroplastic adaptations between at- and below-level thalamic and cortical neurons can contribute mechanistically to below-level pain. Following SCI of humans, an expanded region of Vc includes cells responsive to at-level stimulation (68;85;112). Electrical stimulation of cells in this region through a microelectrode elicits a pain sensation more reliably if the projected field (PF: area of sensation during stimulation) is within a below-level portion of the body that is chronically painful (68). The PF sensations are characterized as burning and are referred both to RF locations of cells at the tip of the electrode and to an insensitive, below-level area. Altered processing of nociception following SCI also is apparent within the primary somatosensory cortex (SI). A portion of the somatotopic map becomes expanded and comprised of cells that are hyperactive and hyper-responsive to stimulation within dermatomes at- and slightly above-level (83;221). Images of SI show that at-level stimulation activates cells in the somatotopically appropriate region of SI plus distant cells in SI that normally would respond only to below-level stimulation (83). Restructuring of the SI somatotopic map to connect abnormally active at-level neurons with below-level neurons is attributed to growth (sprouting) of intracortical connections (83;106;175;221). Once

these connections are established, SCI patients with at-level allodynia experience more intense belowlevel pain (54). The magnitude of below-level pain in these cases is significantly related to the extent of the neuroplastic adaptation of SI to deafferentation (221). An important question concerns the mechanism (driving force) for expansion of the VPL and SI areas given over to cells with at-level RFs. A likely candidate is abnormal activity that propagates rostrally from spinal gray matter injury. Accordingly, application of lidocaine to the rostral border of an SCI injury can relieve below-level pain (115). 22. Are there sensory risk factors for below-level SCI pain? Is below-level pain preceded reliably by sensory events, indicating that it is not spontaneous (55;119)? SCI pain can be initiated by physical jarring, joint movements, touch, cold, weather, physical activity, a full bladder, disturbance of bowel function (22;30;110), and by imagined movements of a foot (74). Even pain described as steady can be enhanced by activity and relieved by rest (170). However, the frequency and reliability of triggering events for SCI pain have not been determined. Questions of triggering apply specifically to incomplete/discomplete SCI. For example, does activation of ascending axons spared by SCI develop the capacity over time to synchronize the discharge of partially deafferented cortical neurons, producing pain? Hypersensitivity in association with development of below-level SCI pain has been documented in a prospective investigation (229). A cohort of 28 patients was evaluated early (2 to 4 weeks) and at 1 to 2.5 and 2.6 to 6 months following traumatic spinal injury above T10. Thirteen individuals developed chronic below-level pain, at an average of 3.8+2 postsurgical months, and 15 individuals did not have chronic pain within the duration of the study. Overall, below-level, dynamic mechanical allodynia and thermal hyperpathia were present during the first two test periods for patients who developed chronic pain, compared to patients who did not. These differences between groups increased during the third test period. Thus, psychophysical demonstrations of increased pain sensitivity were associated with and appeared to predate development of chronic pain for patients who sustained incomplete/discomplete spinal injuries. Did ongoing, neuropathic pain develop for patients in the above study with hypersensitivity, or did nociceptive pain become chronic? It is possible that hyperpathic/nociceptive pain becomes more readily triggered over time and/or is enduring once triggered. Prospective evaluation and reporting on

individual SCI patients could determine whether each case of chronic pain is nociceptive/hyperpathic or neuropathic. 23. Thalamocortical systems for pain An understanding of the avenues for ascending nociceptive conduction above the spinal cord is evolving in complexity, bringing numerous thalamic nuclei and cortical areas into consideration, mechanistically, for different aspects of SCI pain. Early anatomical and physiological descriptions of medial lemniscal and spinothalamic projections to VPL (Vc) and S1 for detection and discrimination of somatosensations (216) have been extended and modified, particularly for nociception. Cortical imaging and neurophysiological recordings have separated the classic S1 target for myelinated nociception (the deep dorsal horn to VPL and areas 3b and 1) and a separate S1 destination for unmyelinated nociception (the superficial dorsal horn to the posterior group of thalamic nuclei and area 3a) (172;173;198). Connections to cortical pain matrices subserve attention to pain and emotional/motivational accompaniments of pain (90). A substantial literature reveals thalamic sites for integrative processing of spinothalamic and spinoreticulothalamic input (10;24;156). Secondary thalamic nuclei with nociceptive input include: VPI, the pulvinar, the posterior nuclear group, centralis lateralis, the dorsomedial nucleus and the thalamic reticular nucleus, at a minimum. The possibility exists that chronic pain can result from abnormal activation of any of these thalamic nuclei and their cortical projections. For example, clinical reports have provided evidence for near abolishment of chronic pain following surgical lesions of: thalamic nucleus centralis lateralis (92), cortical area 3a (144;198;214), and the anterior cingulate gyrus (154). 24. Spontaneous neuronal discharge and ongoing pain? Hyperactivity of deafferented neurons has been considered as a possible mechanism for (source of) chronic neuropathic pain. However, spontaneous neuronal hyperactivity as bursting discharge occurs with or without associated pain (171). Thalamic bursting, characterized by calcium spiking, can be associated with chronic pain (68;85;111), but this pattern of activity is intrinsic to the thalamus (103), occurring normally during slow-wave sleep (38). Also, spontaneous discharge among deafferented neurons lacks coherence. It is not synchronized among functionally related neurons in sequences that approximate normal responses to natural stimulation (174). Recurrent thalamocortical and corticothalamic interactions among nocireceptive neurons involved in sensory coding (24) must be

chaotic if the activity of these neurons is not timed in relation to some event or series of events. Accordingly, no variety of below-level pain has been associated with a specific pattern and location of spontaneous activity (21;22;50;55;75;204;207). A clear relationship between the timing and location of synchronous bursting and the timing and location of pain (34) must be evident to indicate causality. 25. Arousal by and attention to chronic SCI pain There are indications that arousal by chronic pain, and attention to it, is exaggerated for SCI patients. SCI with interruption of the spinothalamic tract partially deafferents the brain stem reticular formation, presumably establishing hyperactivity and hypersensitivity within the reticular activating system. Arousal by and attention to chronic pain could then be enhanced by discomplete/incomplete SCI injuries that spare triggers from spinoreticular input. The importance of spinoreticular activation for arousal by pain has been reinforced by recordings from 14 sites within the cortical pain matrices (11;61). The first set of cortical regions activated by brief laser stimulation of thermal afferents involves spinothalamic processing in S1, the posterior insula and the posterior parietal and supplementary motor cortex. Activation of these structures does not initiate conscious perception of pain. Later activation of a second set of structures by spinothalamic and spinoreticulothalamic input is required for pain perception (64). These structures include the anterior insula, anterior cingulate, lateral prefrontal and posterior parietal cortices. According to this characterization, spinoreticular activation contributes essentially to arousal and conscious perception of pain. Cortical imaging has revealed that chronic pain is associated preferentially with activation of prefrontal and cingulate cortical areas that mediate attention and are components of the default mode network (DMN) (59;105;165;228). The DMN is implicated in perseverative rumination about pain and its consequences, as observed with catastrophizing, which increases SCI pain (28;127). 26. Prefrontal modulation of pain Activation of the prefrontal cortex by nociceptive input not only directs an individual’s attention to the pain (138), but the pain is modulated. Pain intensity is enhanced or decreased in accord with expectations. Well known examples are placebo or nocebo effects when positive or negative treatment effects are expected (44;143). Also, modulation is evident when pain is evoked and evaluated in

alternating series of increasing and decreasing intensities. Pain is enhanced within and beyond ascending series and is diminished within and beyond descending series (133;197;199). Pain is enhanced as a warning, and decreasing pain brings relief. Spontaneous increases and decreases (oscillations) in chronic pain that often are observed (58;135) may be enhanced by prefrontal modulation. 27. Summary of SCI pain development Observations of spontaneous or innate reflex behaviors, as a substitute for training laboratory animals to evaluate pain intensity and act to eliminate it accordingly, have not advanced our understanding of pain. Innate behaviors have been observed in the interest of ease, simplicity and speed, sacrificing validity. As it turns out, operant tests and data output can be automated, increasing efficiency by testing multiple subjects simultaneously (e.g., (136;180)) and eliminating the experimenter bias inherent to observational interpretations of innate behaviors. Failures of reflex measures to model human pain have caused clinicians to question the utility of laboratory animal research on pain. In contrast, using operant escape or preference testing to assess the sensitivity of laboratory animals to nociceptive stimulation, SCI pain can be understood as disrupted processing within the cerebral targets of nociceptive projection. The pain sensitivity of laboratory animals is related to that of humans, providing an understanding of cross-species mechanisms of pain hypersensitivity in relation to SCI. Below-level pain sensitivity increases bilaterally following unilateral thoracic cordotomy, progressing from an early contralateral hypoalgesia for monkeys, rats and humans. These results model development of below-level hyperalgesia and chronic pain following thoracic SCI. The behavioral effects of cordotomy are associated with partial denervation of spinothalamic neurons at spinal levels C1-3 and of nocireceptive thalamic and cortical neurons. It is possible that below-level SCI pain rarely develops unless there is some sparing of sensory axonal conduction past a spinal lesion, with activation of partially deafferented and nocireceptive thalamic and cortical neurons. Thus, below-level SCI pain following incomplete or discomplete injuries may be nociceptive, not neuropathic. This possibility was not considered prior to the crucial discovery of discomplete spinal injuries. It is difficult to detect discomplete SCI, requiring repetitive and/or long duration stimulation. Recognition of discomplete SCI may rarify reports of below-level pain from complete spinal injuries.

Spared spinoreticulothalamic axons are implicated in activation of nocireceptive cells deafferented by SCI: 1) The multireceptive composition of spinoreticulothalamic axons provides all categories of somatosensory and visceral input to thalamus and cortex, offering a variety of triggers for activation of partially deafferented neurons. 2) Receptive fields for spinoreticulothalamocortical and C13 spinothalamic cells are large, accounting for the commonly diffuse, poorly localized nature of belowlevel pain. 3) Spinoreticulothalamocortical activation arouses from stimulation at any location with emotional/motivational overtones. Interruption of spinothalamic axons but sparing of some ascending axonal conduction past spinal injuries appears to be necessary but is not sufficient for development of below-level pain. A contributor to neuroadaptive development of below-level pain is transmission of abnormal activity from a spinal site of traumatic injury to partially deafferented thalamic and cortical neurons. Conduction of neuronal hyperactivity away from injured gray matter contributes to recovery of pain sensitivity following cordotomy and is associated with development of below-level pain following SCI. Sources of at-level pain can facilitate below-level pain and may sustain it. Investigators interested in below-level SCI pain can cease looking for spinal mechanisms, unless it can be shown that abnormal spinal processing is passed up the neuraxis to the thalamus and cerebral cortex. However, if patches of gray matter injury occur below the level of traumatic SCI, at-level pain can masquerade as below-level pain. Also, abnormal activity by spinal neurons can activate the sympathetic nervous system and facilitate development of below-level SCI pain (46;47). Hyperactivity of deafferented nocireceptive neurons, in the form of spontaneous, bursting discharge, could be mechanistically related to occurrences of pain, but that possibility does not fit with characteristics of below-level pain. Below-level SCI pain develops at different rates and only for some cases, with locations and characteristics not accounted for by ubiquitous bursting discharge from widespread deafferentation. A more likely neuronal accompaniment of SCI pain is the hypersensitivity that can accompany hyperactivity of deafferented nocireceptive neurons. 28. Mechanistic-based therapeutics for below-level pain and its prevention The mechanisms responsible for development of below-level pain differ for individuals following SCI. Spinal injuries and resultant neuroplastic adaptations are not alike in unknown respects. Individual differences necessitate descriptions of SCI subgroups with similar mechanistic profiles. This can be accomplished by describing individual patients in terms of variables that could influence the

development of below-level pain or characterize it when present. We need to know the descriptive factors that are associated or not with the below-level pain of each individual. Treatments can then be identified that are effective for subgroups of individuals with below-level pain and evidence for a certain mechanism or combination of mechanisms. Clearly, no single treatment will be efficacious for all cases of below-level pain. Advantages of research designs that attend to individual differences have been reviewed elsewhere (185). Prospective investigations following SCI are needed that track whether at- and below-level pain are present and describe their essential features for individuals (laterality, dermatomal distribution, intensity, sensory characteristic(s), whether neuropathic or nociceptive, and temporal features, including constant or intermittent). The timing of below-level pain in the day-night cycle with notations of sleep quality can be informative with respect to relationships with activity and attention/arousal. Occurrences of trigger sensations associated with below-level pain are important to note. Characterizations over time of the spine (compression or tethering) and the spinal lesion (complete, incomplete, discomplete, involved spinal segments, presence of cysts, evidence for inflammation) are essential. Below-level sensory examination should include non-nociceptive tactile stimulation, repetitive heat and cold stimulation and prolonged chemical stimulation. Assessment of at-level pain/paresthesia and/or allodynia/hyperalgesia and techniques to reveal neuronal hyperactivity/hypersensitivity (such as recordings from nerves supplying at-level segments) are needed. Autonomic activation by below-level stimulation of nociceptors could be compared before and after below-level pain onset and with SCI individuals who do not report pain. Imaging of cortical pain processing can detect neuroplastic adaptations. Evaluation of catastrophizing in relation to pain intensity or frequency for individual subjects over time will be relevant to therapeutics. Important questions are addressed by characterization of individuals’ below-level pain in terms of mechanistic factors that precede or coincide with pain when it occurs: How many mechanistically distinct varieties of SCI pain are there, and what are they? Is below-level pain following complete SCI necessarily associated with altered sympathetic activity, or can it result entirelynfrom cortical reorganization, such as sprouting? Is development of below-level pain following incomplete/discomplete SCI always preceded by below-level hypersensitivity? Is activation of C nociceptors an especially potent trigger for below-level pain? Does below-level pain occur only in association with heightened neuronal activity, at-level?

Factors that are present when below-level SCI pain develops can suggest appropriate treatment(s). After associations between mechanistic factors and SCI pain are determined for individuals, then treatments can be selected for patients with similar profiles of factors. For example, if spinal inflammation is detected after below-level pain occurs but was not present before pain is reported, then anti-inflammatory treatment is indicated. Traditionally, anti-inflammatory therapy for SCI pain has involved steroids such as prednisolone (208), but development of side effects over time makes this option unacceptable for chronic use (206). Other methods of reducing spinal inflammation have been proposed on the basis of laboratory animal experiments (42;73;131;142). An understanding of the prefrontal-initiated activation of circuits and transmitters responsible for inhibition of conscious pain sensations could be helpful in guiding therapeutic attempts to control chronic pain. These likely are cerebral systems (e.g., (93;160), rather than brain stem circuits of descending control over nociceptive reflexes. Therapeutics targeted for mechanisms of existing below-level pain of individuals may turn out to be less effective, compared to prevention of pain development. Reversal of neuroplastic adaptations that have established below-level pain may be difficult. Accordingly, clinical trials are needed that involve either chronic administration of one or more agents (e.g., anti-inflammatory), beginning soon after SCI, or an early surgical procedure (e.g. DREZ) designed to attenuate abnormal excitotoxic and inflammatory injury, at-level.

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