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Altered sensations, including pain, are welldocumented consequences associated with spinal cord injury (SCI). Although loss of sensory and motor functions at and below the level of injury is commonly thought to affect individuals with SCI most significantly, secondary consequences that include spasticity, bladder and bowel dysfunctions, infertility, and pain rank among the most difficult conditions to deal with following injury. Understanding the mechanisms responsible for the condition of pain requires one to appreciate the pathological, physiological, neurochemical, and molecular events associated with injury of the spinal cord parenchyma. Over the past 15 years, a systematic examination related to the pathophysiology, clinical characteristics, and treatment of pain associated with SCI has provided insights into the spinal and supraspinal mechanisms associated with the development of atand below-level pain. In this review, experimental studies focusing on the spinal and supraspinal mechanisms associated with pain at and below level will be discussed. [ABSTRACT FROM AUTHOR]

In recent years, the disappointing history of translation in pain research has undergone significant scrutiny. The escalation of knowledge and understanding related to presumed pain in neuropathic and inflammatory animal models contrasted with the unsatisfactory record of "bench-to-bedside" translation has raised many questions about the validity and clinical relevance of preclinical models and methods of behavioral assessment. Although many opinions have been expressed one of the overriding concerns and greatest barriers to the widening gap between preclinical research and the development of new interventions has been the underappreciated distinction between pain and nociception. As a result of these shortcomings, the distance between mechanism-based research and patient-centered product development has been referred to as the "valley of death." The reasons for the disappointing record of translation are many and easy to point out, but the changes needed and the strategies necessary to accomplish translational goals are much more difficult to identify. One of the challenges of translational pain research that has garnered a lot of attention relates to strategies of behavioral assessment which, with few exceptions, has remained basically unchanged for more than 3 decades. Other issues important to the discussion include but are not limited to the predictive validity of preclinical models, and the neglect of gender, age, and comorbidities in the design of preclinical studies. On the clinical side, the lack of sanitization of phenotypes in clinical trials has also contributed to the insufficient success of efforts to translate basic research to the clinic. The current review will discuss these and other issues believed to have contributed to the existing obstacles and challenges facing pain research along with making recommendations for the future., Perspective: In this review the challenges of preclinical pain research and the reasons for the disappointing record of translation are examined. Important to this discussion is recognizing the scope of clinical characteristics associated with chronic pain conditions and the need for more clinically relevant models and methods of pain assessment., (Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

Flexion/withdrawal reflexes are attenuated by spinal, intracerebroventricular (ICV) and systemic delivery of cholinergic agonists. In contrast, some affective reactions to pain are suppressed by systemic cholinergic antagonism. Attention to aversive stimulation can be impaired, as is classical conditioning of fear and anxiety to aversive stimuli and psychological activation of stress reactions that exacerbate pain. Thus, in contrast to the suppressive effects of cholinergic agonism on reflexes, pain sensitivity and affective reactions to pain could be attenuated by reduced cerebral cholinergic activation. This possibility was evaluated in the present study, using an operant test of escape from nociceptive thermal stimulation (10 °C and 44.5 °C) before and after destruction of basal forebrain cholinergic neurons. ICV injection of 192 IgG-saporin produced widespread loss of basal forebrain cholinergic innervation of the cerebral cortex and hippocampus. Post-injection, escape from thermal stimulation was decreased with no indication of recovery for upto 19 weeks. Also, the normal hyperalgesic effect of sound stress was absent after ICV 192-sap. Effects of cerebral cholinergic denervation or stress on nociceptive licking and guarding reflexes were not consistent with the effects on operant escape, highlighting the importance of evaluating pain sensitivity of laboratory animals with an operant behavioral test. These results reveal that basal forebrain cholinergic transmission participates in the cerebral processing of pain, which may be relevant to the pain sensitivity of patients with Alzheimer's disease who have prominent degeneration of basal forebrain cholinergic neurons., (Copyright © 2016 IBRO. All rights reserved.)

Background: Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long-term evaluation of individual subjects because of the variability in effect over time for humans., Methods: Rats were trained on an operant escape task that determined their preference for occupancy of a brightly lit compartment versus a dark compartment with a floor preheated to 10, 32 or 44.5 °C. Following determination of baseline preferences, the animals received extradural implantation of a small piece of polymer in the thoracic spinal canal. The polymer narrowed the spinal canal and compressed the spinal cord. Post-operative tests of escape preference were conducted over 23 weeks (experiments 1 and 2) and 62 weeks (experiment 3), permitting statistical evaluation of individual effects., Results: Spinal stenosis/compression produced hyperalgesia for cold and/or heat stimulation (17 animals; 77%), no post-operative change in sensitivity (4 animals) or hypoalgesia for cold or heat (2 animals). When hyperalgesia occurred, it developed gradually over 4 months. Following removal of the polymer in experiment 3, heat sensitivity returned to baseline levels for four of four animals that had been hyperalgesic when the polymer was in place, but cold hyperalgesia was retained for four of five animals. Overall, post-operative changes in cold and heat sensitivity were not strongly related, indicating that different mechanisms were responsible for enhanced sensitivity to 10 and 44.5 °C., Conclusions: Histology revealed that hyperalgesia occurred when there was: (1) damage to spinal white matter; or (2) cystic cavitation; or (3) compression and distortion of the spinal cord without an obvious loss of grey or white matter., (© 2015 European Pain Federation - EFIC®)

Testing of reflexes such as flexion/withdrawal or licking/guarding is well established as the standard for evaluating nociceptive sensitivity and its modulation in preclinical investigations of laboratory animals. Concerns about this approach have been dismissed for practical reasons - reflex testing requires no training of the animals; it is simple to instrument; and responses are characterized by observers as latencies or thresholds for evocation. In order to evaluate this method, the present review summarizes a series of experiments in which reflex and operant escape responding are compared in normal animals and following surgical models of neuropathic pain or pharmacological intervention for pain. Particular attention is paid to relationships between reflex and escape responding and information on the pain sensitivity of normal human subjects or patients with pain. Numerous disparities between results for reflex and operant escape measures are described, but the results of operant testing are consistent with evidence from humans. Objective reasons are given for experimenters to choose between these and other methods of evaluating the nociceptive sensitivity of laboratory animals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Studies of humans, monkeys and rodents have implicated combined gray and white matter damage as important for development of chronic pain following spinal cord injury (SCI). Below-level chronic pain and hyperalgesia following injury to the spinal white matter, including the spinothalamic tract (STT), can be enhanced by excitotoxic influences within the gray matter at the site of SCI. Also, excitotoxic injury of thoracic gray matter without interruption of the STT results in below-level heat hyperalgesia. The present study evaluates the possibility that thoracolumbar gray matter injury increases sensitivity to nociceptive heat stimulation by altering spinal sympathetic outflow. Thermal preferences of rats for heat (45 °C) versus cold (15 °C) were evaluated before and after thoracolumbar injections of quisqualic acid (QUIS). A pre-injury preference for heat changed to a post-injury preference for cold. Systemic activation of the sympathetic nervous system by restraint stress decreased the heat preference pre-injury and increased the cold preference post-injury. The heat aversive effect of stress was magnified and prolonged post-injury, compared to pre-injury. Also, peripheral sympathetic activation by nociceptive stimulation was evaluated pre- and post-injury by measuring thermal transfer through a hindpaw during stimulation with 44.5 °C. Skin temperature recordings revealed enhanced sympathetic activation by nociceptive heat stimulation following spinal QUIS injury. However, increased sympathetic activation with peripheral vasoconstriction should enhance cold aversion, in contrast to the observed increase in heat aversion. Thus, peripheral sympathetic vasoconstriction can be ruled out as a mechanism for heat hyperalgesia following excitotoxic gray matter injury.

Neuropathic pain challenges healthcare professionals and researchers to develop new strategies of treatment and experimental models to better understand the pathophysiology of this condition. In the present study, the efficacy of gabapentin on thermal sensitivity following spinal nerve ligation and spinal cord compression was evaluated. The method of behavioral assessment was a well-validated cortically dependent operant escape task. Spinal nerve ligation produced peripheral neuropathic pain whereas spinal cord compression, achieved with an expanding polymer placed extradurally, produced a condition of central neuropathic pain. Changes in thermal sensitivity were also observed in animals undergoing nerve ligation surgery without nerve injury. Gabapentin (50 and 100 mg/kg) significantly reduced thermal sensitivity to 10 and 44.5 °C in surgically naive animals as well as those undergoing spinal nerve ligation and spinal cord compression. In conclusion, an operant method of behavioral assessment was used to show that spinal nerve ligation and spinal cord compression produced increases in sensitivity to noxious cold and heat stimuli. A decrease in thermal sensitivity was observed following administration of gabapentin. The results achieved with these methods are consistent with the clinical profile of gabapentin in treating conditions of neuropathic pain.

Study Design: Discussion of issues and development of consensus., Objective: Present the background, purpose, development process, format and definitions of the International Spinal Cord Injury Pain (ISCIP) Classification., Methods: An international group of spinal cord injury (SCI) and pain experts deliberated over 2 days, and then via e-mail communication developed a consensus classification of pain after SCI. The classification was reviewed by members of several professional organizations and their feedback was incorporated. The classification then underwent validation by an international group of clinicians with minimal exposure to the classification, using case study vignettes. Based upon the results of this study, further revisions were made to the ISCIP Classification., Results: An overall structure and terminology has been developed and partially validated as a merger of and improvement on previously published SCI pain classifications, combined with basic definitions proposed by the International Association for the Study of Pain and pain characteristics described in published empiric studies of pain. The classification is designed to be comprehensive and to include pains that are directly related to the SCI pathology as well as pains that are common after SCI but are not necessarily mechanistically related to the SCI itself., Conclusions: The format and definitions presented should help experienced and non-experienced clinicians as well as clinical researchers classify pain after SCI.

Study Design: International validation study using self-administered surveys., Objectives: To investigate the utility and reliability of the International Spinal Cord Injury Pain (ISCIP) Classification as used by clinicians., Methods: Seventy-five clinical vignettes (case histories) were prepared by the members of the ISCIP Classification group and assigned to a category by consensus. Vignettes were incorporated into an Internet survey distributed to clinicians. Clinicians were asked, for each vignette, to decide on the number of pain components present and to classify each using the ISCIP Classification., Results: The average respondent had 86% of the questions on the number of pain components correct. The overall correctness in determining whether pain was nociceptive was 79%, whereas the correctness in determining whether pain was neuropathic was 77%. Correctness in determining if pain was musculoskeletal was 84%, whereas for visceral pain, neuropathic at-level spinal cord injury (SCI) and below-level SCI pain it was 85%, 57% and 73%, respectively. Using strict criteria, the overall correctness in determining pain type was 68% (versus an expected 95%), but with maximally relaxed criteria, it increased to 85%., Conclusions: The reliability of use of the ISCIP Classification by clinicians (who received minimal training in its use) using a clinical vignette approach is moderate. Some subtypes of pain proved challenging to classify. The ISCIP should be tested for reliability by applying it to real persons with pain after SCI. Based on the results of this validation process, the instructions accompanying the ISCIP Classification for classifying subtypes of pain have been clarified.

Objective: Preclinical studies of pain and aging represent an area of research where considerations of age, strain, gender, and method of behavioral assessment are but some of the challenges that must be addressed. The results of studies related to the impact of age on pain sensitivity have ranged from increased to decreased sensitivity to no change. Examining the design of these studies one discovers that cross-sectional designs using animals of different ages have been used to evaluate age-related effects in normal animals as well as animals with inflammatory and neuropathic pain conditions. In the present review a summary of these studies is presented along with a discussion of potential mechanisms responsible for changes that have been described., Outcome Measures: The dominant method of behavioral assessment in the majority of studies involving rodents has been reflex-based strategies that unfortunately do not reveal the same effects of experimental manipulations known to affect pain sensitivity in humans. A comparison of results obtained with reflex-based methods versus those obtained with cortically dependent operant methods reveals significant differences., Conclusions: Increases in pain sensitivity under different experimental conditions have been suggested to result from age-related anatomical, physiological, and biochemical changes as well as compensatory changes in homeostatic mechanisms and intrinsic plasticity of somatosensory pathways involved in the processing and perception of pain. Other factors that may contribute to the impact of age on pain sensitivity include dysregulation of the hypothalamic-pituitary-adrenal axis and changes in autonomic function that occur with advancing age. In the future translational research in the field of pain and aging will need to focus on establishing clinically relevant animal models and assessment strategies to evaluate the causal relationships between the biological changes associated with advancing age and the varied behavioral changes in pain sensitivity., (Wiley Periodicals, Inc.)

Effects of excitotoxic injury to the thoracic gray matter on sensitivity to below-level nociceptive stimulation were evaluated for female and male Long-Evans rats. Operant escape and lick/guard (L/G) reflex responses to thermal stimulation were evaluated before and for 13-15 weeks after: 1) injections of quisqualic acid (QUIS) into the thoracic gray matter (T8-9), 2) laminectomy and spinal exposure and penetration without injection (sham) or 3) no surgical procedure (control). L/G responding to heat stimulation (44 °C) was unaffected for females and males following thoracic QUIS injections. Similarly, male escape performance was not significantly altered for 44 °C or 10 °C stimulation after QUIS injections or sham surgery. However, escape testing following QUIS and sham injections revealed increased heat sensitivity (44 °C) and decreased cold sensitivity (10 °C) for females. This selective effect is indicative of altered sympathetic activation by the thoracic injections. The effect of sham surgery suggests that female rats are vulnerable to ischemic injury during exposure and manipulation of the spinal cord. Escape from nociceptive heat and cold sensitivity of control males and females was unchanged over 13-15 weeks of testing., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Dr Robert Yezierski received his PhD in Physiology from West Virginia University (WV, USA). He completed postdoctoral training at the Marine Biomedical Institute in Galveston (TX, USA). Dr Yezierski joined the faculty in the Department of Anatomy at the University of Mississippi Medical Center in Jackson (MS, USA) in 1981 where he carried out studies related to the anatomy, physiology and pharmacology of spinal neurons projecting to different targets of the mesencephalon (spinomesencephalic tract). In 1987, he assumed the position of Associate Professor in the Department of Neurological Surgery and The Miami Project to Cure Paralysis at the University of Miami (FL, USA) where he initiated studies related to the condition of pain and abnormal sensation associated with spinal cord injury. Dr Yezierski created a program in pain research at The Miami Project and was co-chair of an international task force related to the condition of spinal cord injury pain along with organizing numerous symposia and workshops related to this topic. In 2001 Dr Yezierski was appointed Professor and Director of the Comprehensive Center for Pain Research at the University of Florida (FL, USA). Dr Yezierski's current research is dedicated to understanding the mechanisms underlying the onset and progression of abnormal sensation including pain with advancing age. His research program is multidisciplinary, combining a variety of anatomical, molecular, pharmacological, physiological and behavioral techniques.

Age-dependent changes in thermal sensitivity were evaluated with reflex- and operant-based assessment strategies in animals ranging in age from 8 to 32 months. The impact of inflammatory injury on thermal sensitivity was also determined in animals of different ages. The results showed that operant measures of escape behavior are needed to demonstrate significant changes in thermal sensitivity across the life span of female Long-Evans rats. Increased escape from both heat (44.5 degrees C) and cold (1.5 degrees C-15 degrees C) was observed for older animals, with a greater relative increase in sensitivity to cold. Physical performance deficits were demonstrated with aging but were not associated with changes in escape responding. Reflex responding to cold stimulation was impaired in older animals but was also influenced by physical disabilities. Reflex responding to heat was not affected by increasing age. Inflammation induced by formalin injections in the dorsal hindpaw increased thermal sensitivity significantly more in older animals than in their younger counterparts.

Activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) are implicated in the pathophysiology of spinal cord injury (SCI). However, the specific functions of individual ERK isoforms in neurodegeneration are largely unknown. We investigated the hypothesis that ERK2 activation may contribute to pathological and functional deficits following SCI and that ERK2 knockdown using RNA interference may provide a novel therapeutic strategy for SCI. Lentiviral ERK2 shRNA and siRNA were utilized to knockdown ERK2 expression in the spinal cord following SCI. Pre-injury intrathecal administration of ERK2 siRNA significantly reduced excitotoxic injury-induced activation of ERK2 (p < 0.001) and caspase 3 (p < 0.01) in spinal cord. Intraspinal administration of lentiviral ERK2 shRNA significantly reduced ERK2 expression in the spinal cord (p < 0.05), but did not alter ERK1 expression. Administration of the lentiviral ERK2 shRNA vector 1 week prior to severe spinal cord contusion injury resulted in a significant improvement in locomotor function (p < 0.05), total tissue sparing (p < 0.05), white matter sparing (p < 0.05), and gray matter sparing (p < 0.05) 6 weeks following severe contusive SCI. Our results suggest that ERK2 signaling is a novel target associated with the deleterious consequences of spinal injury.

In our previous studies, psychological stress was shown to enhance operant escape responding of male and female rats. The stressors that produced hyperalgesia were physical restraint and social defeat. Nociceptive input also elicits stress reactions, generating the prediction that pain would facilitate pain under certain circumstances. For example, the usual method of evaluating stress in laboratory animals is to test for effects after termination of the stressor. Accordingly, operant escape performance of male and female rats was evaluated during two successive trials involving nociceptive thermal stimulation. The intent was to determine whether nociceptive sensitivity differed on first trials and during pain-induced stress on second trials. Compared to a first trial of 44.5 degrees C stimulation, escape responding increased during a second trial of 44.5 degrees C stimulation (preceded by an escape trial of 10 degrees C). Similarly, escape from cold (10 degrees C) was enhanced when preceded by escapable 44.5 degrees C stimulation. Thus, prior nociceptive stimulation enhanced escape from aversive thermal stimulation. Facilitation of pain by a preceding pain experience is consistent with stress-induced hyperalgesia and contrasts with other models of pain inhibition by concurrent nociceptive stimulation.

Unlabelled: Icilin induces wet dog shakes (WDS) in rodents when injected systemically and activates the cold receptor TRPM8 and putative cold receptor TRPA1. It is assumed that WDS reflect an enhanced cold sensitivity; however, none have examined the relationship between WDS and cutaneous cold sensitivity following systemic icilin. In this study, we sought to characterize the effect of systemic and central icilin administration on WDS and thermal preference with either hindpaw or facial stimulation. It was found that a low dose of icilin (.025 mg), which transiently elevated WDS, decreased preference for cold with hindpaw stimulation (15 and 45 degrees C) when administered ip or it. Intracisternal administration of this dose produced similar results for facial stimulation (10 and 48 degrees C), but had no effect when administered ip. In contrast a high dose of icilin (.25 mg), which persistently elevated WDS, strongly increased preference for cold with hindpaw stimulation and had no effect on thermal preference with facial stimulation. These findings indicate that at the low concentration, systemic and central icilin enhances cold sensitivity, likely via TRPM8 and TRPA1 activation. In contrast, systemic icilin at the high concentration produces peripheral and/or central effects that diminish cold sensitivity, while WDS is maintained at a persistent rate., Perspective: Icilin is a unique compound that produces dissociable effects on an innate behavior (WDS) and on operant behaviors related to thermal perception. This compound could help clarify the relationship between peripheral cold transduction and the central induction of thermogenesis and nocifensive behaviors, as well as alterations that produce pathological pain.

Higher-order processing of nociceptive input is distributed in corticolimbic regions of the brain, including the anterior cingulate, parieto-insular and prefrontal cortices, as well as subcortical structures such as the bed nucleus of stria terminalis and amygdala. In addition to their role in pain processing, these regions encode or modulate emotional, motivational and sensory responses to stress. Thus, pain and stress pathways in the brain intersect at cortical and subcortical forebrain structures. Accordingly, previous work has shown that acute restraint stress in female rats induces heat hyperalgesia in a forebrain-dependent operant test of thermal escape. In the present study, we investigated the effects of social defeat stress in male rats on the operant escape task, as well as in a test of nociceptive thermal preference. After establishing baseline behaviors in these tests, separate groups of rats were socially defeated by dominant "resident" male rats. They were tested for thermal preference after 5 successive social defeat sessions. Escape from cold, heat and a neutral warm temperature also was evaluated after social defeat. Defeated rats exhibited a significant increase in cold preference after social defeat compared to the baseline. In the escape task, the rats exhibited increased escape from warm and nociceptive cold and heat temperatures. Thus, chronic social stress produces hyperalgesia for both hot and cold stimuli in male rats, suggesting a mutually facilitatory cross-regulation between central pathways regulating stress and pain.

Unlabelled: Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation., Perspective: This study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.

Opioids are the most effective compounds available for the relief of pain, yet there are a number of side effects that are of great concern to clinicians. For example, opioids are powerful reinforcers, and the treatment of pain using opioids could lead to the development of addiction. In addition, there is an increasing body of literature demonstrating that the repeated administration of opioids could lead to a phenomenon called opioid-induced hyperalgesia (i.e., increased sensitivity to painful stimulation). Studies examining these potential adverse effects are necessary in the development of novel analgesics. Furthermore, most studies of pain sensitivity and pain relief use reflex-based procedures to identify analgesics; however, it is argued here that operant-based procedures provide measures that are more analogous to the human condition (i.e., the mechanisms of pain are similar to those in humans) and should be useful in the assessment of novel analgesics. A series of studies examining the effects of opioids and the influence of variables such as age are discussed to demonstrate the utility of this approach., (Copyright (c) 2008 APA, all rights reserved.)

Subcutaneous formalin injection has been used extensively to evaluate acute effects (over several hours) of chemical nociceptive stimulation on nociceptive reflexes. Also, a persistent hyperreflexia for mechanical and thermal stimulation, lasting 3 weeks after formalin injection, has been revealed and related to microglial activation in the spinal dorsal horn. The present study demonstrates more prolonged effects of formalin injection, lasting 6 weeks, on operant escape from nociceptive thermal stimulation. Operant escape requires cerebral processing of nociceptive input and can detect effects that are not limited to spinal or spinal-brain stem-spinal reflex circuits. Compared with rats injected with saline, escape responding to 44.5 degrees C and 47 degrees C stimulation was increased after bilateral s.c. injection of 5% formalin into the dorsal hind paws. The hyperalgesia outlasted visible signs of trauma (e.g. paw edema). Responses to 36 degrees C were not altered after formalin injection, providing a control for effects of the peripheral injury on activity levels or exploratory tendencies. Skin temperature recordings from the forepaws and contralateral hind paw during 44.5 degrees C stimulation of the left hind paw provided an indirect measure of cutaneous blood flow in formalin- and saline-injected animals. Normal reductions in skin temperature during thermal stimulation were attenuated (nearly eliminated) at 1 and 2 weeks after formalin injection and partially recovered by 10 weeks. Thus, formalin-induced tissue injury produced a long-term secondary hyperalgesia, accompanied by a reduced sympathetic responsivity. The similar time-course for these phenomena suggests that there are mechanistic linkages between focal injury, autonomic dysregulation and enhanced pain sensitivity.

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.

Forebrain activation patterns in normal and spinal-injured Sprague-Dawley (SD) rats were determined by measuring regional cerebral blood flow as an indicator of neuronal activity. Data are compared to our previously published findings from normal and spinal-injured Long-Evans (LE) rats and reveal a striking degree of overlap, as well as differences, between strains in the basal (unstimulated) forebrain activation in normal animals. Specifically, 81% of the structures sampled showed similar activation in both strains, suggesting a consistent and identifiable pattern of basal cerebral activation in the rat. LE controls showed significantly greater basal activation in the remaining structures compared to SD control group, including the anterior dorsal thalamus, basolateral amygdala, SII cortex, and the hypothalamic paraventricular nucleus. In contrast, spinal cord injury (SCI) resulted in strain-specific changes in forebrain activation categorized by structures that showed significant increases in: (1) only LE SCI rats (posterior, ventrolateral, and ventroposterolateral thalamic nuclei); (2) only SD SCI rats (anterior-dorsal and medial thalamus, basolateral amygdala, cingulate and retrosplenial cortex, habenula, interpeduncular nucleus, hypothalamic paraventricular nucleus, periaqueductal gray); or (3) both strains (arcuate nucleus, ventroposteromedial thalamus, SI and SII somatosensory cortex). These results provide information related to the remote, i.e. supraspinal, effects of spinal cord injury and suggest that genetic differences play an important part in the forebrain response to such injury. Brain activation studies therefore provide a useful tool in understanding the full extent of secondary consequences following spinal injury and for identifying potential central mechanism responsible for the development of pain.

The role of the ERK1/2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury (SCI) was examined. Specifically, phosphorylation of ERK1/2, activation of transcription factors NF-kB, ELK-1, and CREB, and gene expression of the neurokinin-1 receptor and NMDA receptor subunits NR1 and NR-2A were investigated. Excitotoxic injury was produced by intraspinal injection of quisqualic acid (QUIS) in male Sprague-Dawley rats. Western blots were used to evaluate phosphorylation and activation of ERK1/2 and transcription factors using phospho-specific or total antibodies. Real-time PCR was used to evaluate gene expression of NK-1R, NR-1, and NR-2A. Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior. Excitotoxic spinal injury resulted in: (1) increased phosphorylation of ERK1/2; (2) increased activation of NF-kB and phosphorylation of ELK-1; and (3) increased gene expression for the NK-1 receptor and NR1 and NR-2A subunits of the NMDA receptor. Blockade of the ERK cascade with the MEK inhibitor PD98059 inhibited phosphorylation of ELK-1, activation of NF-kB and gene expression of NR1, NR-2A and NK-1R, and prevented the development of excessive grooming behavior. The results have shown that excitotoxic spinal injury leads to the injury-induced activation of the ERK-->ELK-1 and NF-kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain. Blockade of this intracellular kinase cascade prevented the onset of injury-induced pain behavior.

Background and Purpose: Although high-resolution MR imaging is a valuable diagnostic tool, in vivo MR imaging has not yet been compared with in vitro MR imaging and histologic techniques following experimental spinal cord injury (SCI). The goal of the present study was to evaluate the feasibility of using in vivo MR imaging, in vitro MR imaging, and histologic techniques to study pathologic changes associated with excitotoxic SCI at a single time point. These results are important for future research using in vivo MR imaging to study the temporal profile of pathologic changes following SCI., Methods: Rats received intraspinal injections of quisqualic acid at the T12-L2 spinal level. In vivo T1- and T2-weighted and dynamic contrast-enhanced MR images were collected 17-24 days postinjury. Once completed, spinal cords were removed and in vitro MR microscopy and histologic assessment were performed. MR images were collected using 4.7-T (in vivo) and 14.1-T magnets (in vitro)., Results: Pathologic changes--including hemorrhage, neuronal loss, cavities, and central canal expansion--were visible in T2-weighted in vivo MR images. Evaluation of the blood-spinal cord barrier after injury with contrast agent enhancement showed no disruption at the time points evaluated. In vitro MR images and histologic evaluation confirmed pathologic details observed in vivo., Conclusion: Results show that high-resolution in vivo MR imaging has the potential to be used in studying the progression of pathologic changes at multiple time points following SCI. This strategy may provide a way of studying structure-function relationships between therapeutic interventions and different pathologic characteristics of the injured spinal cord.

The condition of pain after spinal cord injury (SCI) affects the life quality of nearly 70% of individuals with SCI. Clinical studies over the past decade have provided important insights into the complexities of the clinical and psychosocial characteristics of this debilitating consequence of SCI. The use of experimental models developed to study at-level or below-level pain has provided an appreciation for the mechanism(s) responsible for the onset and progression of these conditions. Important to the studies related to SCI pain has been the focus on the molecular, biochemical, anatomical, and functional consequences of SCI that have identified potential therapeutic targets for the design of novel treatment strategies., (Copyright 2005 S. Karger AG, Basel)

Using a conjugate of substance P and the ribosome-inactivating protein saporin, neurons expressing the neurokinin-1 receptor in lamina I of the spinal cord were targeted to determine their role in the expression of a spontaneous pain behavior following intraspinal injections of quisqualic acid in the rat. Treatment was carried out at the time of injury in order to prevent the onset of the behavior, and following onset in order to evaluate the potential clinical utility of this intervention. Treatment at the time of injury resulted in significant decreases in onset-time and severity of pain behavior, while treatment at the time of onset led to a significant reduction of the spontaneous self-directed behavior. The results suggest that the substrate for at-level pain following spinal cord injury includes a population of spinal neurons expressing the neurokinin-1 receptor in the superficial laminae of the spinal cord.

Acute stress has been shown to increase latencies of nociceptive reflexes, and this effect is considered evidence for stress-induced analgesia. However, tests for nociception that rely on motivated operant escape assess cerebral processing of pain and could be modulated independent of reflex responses. We therefore compared the effects of an acute stressor (restraint) on escape responses and lick/guard reflexes to stimulation of the paws by a thermally regulated floor. Testing sessions included a pre-test exposure to 36 degrees C, followed by a test trial in which either escape from 44 or 36 degrees C or reflex responses to 44 degrees C were observed. Behavioral responses to stress were assessed during a three day period, with baseline testing on day 1, post-stress or control testing on day 2, and evaluation of long-term stress effects on day 3. On day 2, half the animals received 15 min of restraint stress, followed by 15-min pre-test and test trials. Licking and guarding responses to thermal stimulation during 44 degrees C test trials were significantly reduced by restraint stress, confirming previously reported stress effects on nociceptive reflexes. In contrast, learned escape responses to the same thermal stimulus were significantly enhanced after stress. The increase in operant sensitivity suggests that acute restraint, a form of psychological stress, produces hyperalgesia for a level of thermal stimulation that preferentially activates C nociceptors. These results are discussed in relation to studies involving physical or psychological forms of stress, different nociceptive stimuli, and assessment strategies used to evaluate thermal pain sensitivity.

The role of NMDA receptor expression and post-translational modification in the pathological and behavioral consequences of injury were examined in rats receiving spinal injections of quisqualate. Spinal cords were removed 3 days following the development of excessive grooming behavior or, if the spontaneous pain-like behavior was not observed, 13 days following injections. Western blots from the spinal tissue demonstrated that non-grooming animals had elevated protein levels of the NR1 subunit of the NMDA receptor. These subunits did not demonstrate an enhanced level of phosphorylation. NR1 protein in grooming rats was not elevated, but there was a significant increase in NR1 serine phosphorylation. These findings suggest that excitotoxic lesions of the spinal cord induce both NR1 expression and NR1 serine phosphorylation. However, the injury-induced excessive grooming behavior is only associated with phosphorylation of the NR1 subunit.

Intraspinal injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS) results in a pathophysiology that leads to excessive grooming behavior, which has been proposed as a model of spontaneous at-level pain after spinal cord injury (SCI). To further characterize the onset and progression of this behavior we evaluated the effects of 3 drugs, agmatine (Agm), interleukin-10 (IL-10), and cyclosporin A (CsA), on different characteristics of this behavior. In these experiments rats were given saline, Agm, CsA10, or CsA20 once daily for 14 days (or a single injection of IL-10) starting either 30 minutes post-QUIS (group 1) or 10 to 18 days post-QUIS when excessive grooming behavior had been established (group 2). In the first group of animals agmatine, IL-10, CsA10, or CsA20 reduced the longitudinal extent of neuronal loss in the spinal cord compared to QUIS-injected animals treated with saline. The behavioral consequences of this effect included the delayed onset of excessive grooming behavior, reduction in the area of skin targeted for excessive grooming, and reduced grooming severity. Animals treated at the time of excessive grooming onset showed significantly reduced grooming area, grooming severity, and neuronal loss in the spinal cord compared to QUIS animals treated with saline. In conclusion, systemic administration of Agm, IL-10, or CsA significantly delayed the onset and reduced the severity of a spontaneous pain-like behavior. These effects are believed to be due, in part, to the neuroprotective properties of these drugs against QUIS-induced excitotoxicity. The effective treatment of excessive grooming behavior suggests that Agm, IL-10, and CsA modulate ongoing cellular events responsible for the progression of this behavior.

Background and Purpose: Spinal cord injury (SCI) results in a number of consequences; one of the most difficult to manage is chronic neuropathic pain. Thus, defining the potential neural and biochemical changes associated with chronic pain after SCI is important because this may lead to development of new treatment strategies. Prior studies have looked at the thalamus, because it is a major sensory relay station. The purpose of our study was to define alterations in metabolites due to injury-induced functional changes in thalamic nuclei by using single-voxel stimulated echo acquisition mode MR spectroscopy., Methods: Twenty-six men were recruited: 16 patients with SCI and paraplegia (seven with pain, nine without pain) and 10 healthy control subjects. Pain was evaluated in an interview, which included the collection of information concerning the location, quality, and intensity of pain, carefully identifing the dysesthetic neuropathic pain often seen in SCI. Localized single-voxel (8-cm(3) volume) proton spectra were acquired from the left and right thalami., Results: The concentration of N-acetyl (NA) was negatively correlated with pain intensity (r = -0.678), and the t test showed that NA was significantly different between patients with pain and patients without pain (P =.006). Myo-inositol was positively correlated with pain intensity (r = 0.520); difference between patients with pain and those without pain was almost significant (P =.06)., Conclusion: The observed differences in metabolites in SCI patients with and pain and in those without pain suggest anatomic, functional, and biochemical changes in the thalamic region.

Objectives: To determine how chronic pain after spinal cord injury (SCI) interfered with sleep, exercise, work, household chores, and other daily activities and to define which clinical aspects of pain and psychosocial factors best predicted the extent of interference., Design: Postal survey; follow-up to a previous survey conducted 6 months earlier., Setting: General community., Participants: Individuals (n = 217) with traumatic SCI and chronic pain., Intervention: Subjects answered questions regarding frequency of interference caused by pain on 5 activities: sleep, work, exercise, household chores, and other daily activities. Asked to self-report sadness, fatigue, or anxiety; and to describe location, quality, and intensity of pain., Main Outcome Measures: Demographic data (gender, age, level of injury); sociodemographic data (education, employment); self-reported psychosocial outlook; clinical characteristics of pain: location (drawing), quality (descriptors), and intensity (2 numeric rating scales). Regression analysis., Results: The questionnaire was returned by 65.8% of the sample (217/330). A large number of the participants (77.3%) reported frequent interference caused by pain, ie, "often" to "always" in 1 or more of the 5 activities. The combination of high pain intensity and the use of multiple pain descriptors was significantly associated with frequent interference with falling asleep. Frequent sleep interruption was significantly associated with high pain intensity, male gender, anxiety, and higher age at time of injury. In working individuals, frequent interference due to pain was significantly associated with multiple pain descriptors, anxiety, low level of education, and being older at time of injury., Conclusion: Reported extent of pain interference in various areas of activity is related to clinical symptoms of pain as well as to psychologic and psychosocial factors rather than level of injury. The relationship between frequent interference, pain intensity, and multiple descriptors indicate that individuals experiencing several types of pain of high intensity are more likely than others to experience frequent interference with a variety of daily activities including sleep., (Copyright 2001 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation)

Objective: To define relationships among various clinical characteristics of pain occurring after spinal cord injury (SCI)., Design: Postal survey., Setting: General community., Participants: Of 330 subjects with SCI reporting chronic pain in a previous survey, 217 volunteered., Interventions: Not applicable., Main Outcome Measures: Detailed pain history., Results: Participants had been injured for an average of 8.2 +/- 5.1 years and 55.4% were tetraplegic. Most subjects marked multiple areas on a pain drawing with the back area most frequently (61.8%) indicated. The most common qualities reported were burning pain (59.9%) and aching pain (54.4%). Burning was significantly associated with pain in frontal parts of torso and genitals, buttocks, and lower extremities, whereas aching was significantly associated with neck and shoulders and back. The factor analysis of the relationships between level of injury, location of pain, quality of pain, pain intensity rating, duration of pain breaks, and time for pain onset resulted in 3 groupings: (1) multiple pain locations, burning pain, lower extremity; (2) aching pain, shoulder and neck, cervical injury; and (3) early onset of pain, no breaks to short breaks of pain, and high average pain intensity., Conclusions: Relationships among various clinical features of pain after SCI reveal common clinical patterns important for increased understanding of pain mechanisms and for the design of therapeutic interventions for pain management.

Intraspinal injection of quisqualic acid (QUIS) is associated with the development of spontaneous excessive grooming behavior in male Sprague Dawley rats. To further characterize this pain-like behavior we evaluated the relationship between the onset of this behavior and the rostrocaudal spread of injury-induced neuronal loss in 3 different strains of male rats. The severity and progression of this behavior also were evaluated. Unilateral intraspinal injections of 125 mmol/L QUIS were made in the following groups: Sprague Dawley males (SDMs, n = 21); Long Evans males (LEMs, n = 17); and Wistar Furth males (WFMs, n = 11). Because of differences in grooming characteristics between male and female rats, the modulatory effects of female gonadal hormones also were evaluated in Sprague Dawley females (SDFs, n = 17); bilaterally ovariectomized Sprague Dawley females (OVXs, n = 11); and SDMs treated with either 17-beta-estradiol (50 microg/kg; SDM-Est, n = 9) or progesterone (5 mg/kg; SDM-Pro, n = 11). The results showed that the development of excessive grooming behavior in males of all strains and ovariectomized females is related to the rostrocaudal spread of a specific pattern of neuronal loss in the dorsal horn. Excessive grooming behavior in SDFs was similar in many respects to that found in SDMs; however, SDFs did not show a dependence on the longitudinal extent of injury for the onset of this behavior. The onset, severity, and progression of excessive grooming in OVX females were similar to that found in SDMs. Furthermore, 8 of 9 estradiol-treated SDMs developed severe grooming characterized by an early onset and progressive time course, whereas progesterone treatment delayed the onset of grooming and attenuated its severity and progression. Strain-related differences in some, but not all, grooming characteristics also were observed, eg, WFMs exhibited more aggressive grooming than SDMs or LEMs. In conclusion, the results showed gender, strain, and gonadal hormones influence the onset and progression of injury-induced excessive grooming behavior. A causal relationship also was found between the onset of this behavior and the longitudinal extent of injury.

Objective: Posttraumatic hyperthermia has been demonstrated to worsen neurological outcome in models of brain injury. The purpose of this study was to examine the effects of systemic hyperthermia on locomotor and morphological outcome measures after traumatic spinal cord injury (SCI) in the rat., Methods: After a T10 laminectomy, spinal cord contusions were produced from a height of 12.5 mm onto exposed cords (NYU Impactor; New York University Neurosurgery Laboratory, New York, NY) in adult rats that were divided into three groups. Group 1 (n = 9) underwent whole body hyperthermia (rectal temperature, 39.5 degrees C) 30 minutes postinjury for 4 hours, Group 2 (n = 8) underwent normothermia (rectal temperature, 37 degrees C) 30 minutes postinjury for 4 hours, and Group 3 (n = 10) underwent traumatic SCI with no postinjury thermal treatment. Twice-weekly assessments of locomotor function were made during a 6-week survival period using the Basso-Beattie-Breshnahan locomotor rating scale. Forty-four days after injury, animals were perfused, and their spinal cords serially sectioned. Sections were stained with hematoxylin, eosin, and Luxol fast blue for histopathological analysis. The percentage of tissue damage was quantitatively determined by using computer-aided image analysis., Results: The results showed that 4 hours of postinjury hyperthermia significantly worsened locomotor outcome (final Basso-Beattie-Breshnahan scores were 9.7 +/- 0.3 [Group 1] versus 10.8 +/- 0.4 [Group 2] versus 11.3 +/- 0.3 [Group 3]) and led to an increase in the percentage of tissue damage (32.9 + 3.2% [Group 1] versus 22.3 +/- 2.8% [Group 3])., Conclusion: These data suggest that complications of SCI (e.g., fever, infection) leading to an elevation of systemic temperature may add to the severity of secondary injury associated with traumatic SCI and significantly affect neurological outcome.

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathophysiological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Responses to QUIS-induced injury include an inflammatory component, as well as the development of spontaneous and evoked pain behaviors. We hypothesized that QUIS-induced inflammation and subsequent gene expression contribute to the development and progression of pain-related behaviors and that blockade of inflammation-related gene expression leads to the amelioration of these behaviors. Using the QUIS model of spinal cord injury, we examined whether interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is able to reduce mRNA levels of inflammatory and cell death-related genes leading to a reduction of pain behaviors. The results demonstrate that animals receiving systemic injection of IL-10, 30 minutes following QUIS-induced SCI, showed a significant delay in the onset of excessive grooming behavior, a significant reduction in grooming severity, and a significant reduction in the longitudinal extent of a pattern of neuronal loss within the spinal cord characterized as "grooming-type damage." QUIS injections also resulted in an increase in mRNA levels of interleukin-1 beta (IL-1 beta), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), CD95 ligand (CD95-L, also called FAS-L/APO-1L), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Results of QUIS injury plus IL-10 treatment resulted in a significant downregulation of IL1-beta and iNOS mRNA and these results were supported by Western blot analysis of protein levels following IL-10 treatment. These data suggest that IL-10 reduces inflammation and that targeting injury-induced inflammation is an effective strategy for limiting the extent of neuronal damage following excitotoxic SCI and thus the onset and progression of injury-induced pain behaviors., (Copyright 2001 Academic Press.)

Clinically effective drug treatments for spinal cord injury (SCI) remain unavailable. Agmatine, an NMDA receptor antagonist and inhibitor of nitric oxide synthase (NOS), is an endogenous neuromodulator found in the brain and spinal cord. Evidence is presented that agmatine significantly improves locomotor function and reduces tissue damage following traumatic SCI in rats. The results suggest the importance of future therapeutic strategies encompassing the use of single drugs with multiple targets for the treatment of acute SCI. The therapeutic targets of agmatine (NMDA receptor and NOS) have been shown to be critically linked to the pathophysiological sequelae of CNS injury and this, combined with the non-toxic profile, lends support to agmatine being considered as a potential candidate for future clinical applications.

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury.