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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.

The spinal cord originates from the primitive neural tube, the dorsal horn arises from the alar plate, and the anterior horn arises from the basal plate. The adult cord is located in the spinal dural sac (dura + arachnoid), is continuous with the medulla at the spinal-medulla junction, and extends to spinal levels L1 to L2. Cervical spinal levels are characteristically oval in shape with large amounts of gray matter and white matter, thoracic levels are round with a very reduced gray matter and less white matter, and lumbosacral levels are also round but with large amounts of gray matter and significantly reduced white matter. Spinal nerves are formed by the joining of the posterior root (two sensory components) and ventral root (two motor components) at about the intervertebral foramen. Spinal reflexes are integral parts of most neurologic examinations; all have an afferent limb, an efferent limb, and various degrees of processing of information within the spinal cord. In addition to the sensor-motor features of the spinal reflex, collaterals of primary sensory fibers ascend in spinal tracts that convey information to higher levels of the central nervous system (CNS) for the perception of the sensory data; much of this sensory input may be transmitted to motor centers that give rise to descending tracts to the spinal cord. A wide variety of spinal-related deficits may results from trauma, neurodegenerative and neurotransmitter diseases, and lesions of the CNS above the spinal-medulla junction.

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.

249 ISSN 1758-1869 10.2217/PMT.13.21 © 2013 Future Medicine Ltd Pain Manage. (2013) 3(4), 249–252 There is little doubt that we have experienced far too many quiet moments when it comes to talking about the success of translational pain research. Over the past 5 years a number of articles have been written explaining how good we are at preclinical discovery, and yet, over a period of nearly two decades, we have little to show for it in terms of significant clinical advances in the development of more effective interventions [1]. Perhaps the most compelling commentary on this topic is the growing economic burden of pain and the staggering number of people, from young adults to the elderly, affected by chronic pain [2,3]. These statistics beg the question: if our research strategy is on the right track, then why are the economic and prevalence metrics escalating at a rate faster than at any time in history and why are providers relying on the same basic drug classes to treat pain that have been in place for over a decade? Given a not-so-successful track record in translational research, one is tempted to ask the question, “Are we really that stubborn?” or, as some have asked, “Are we just smart people making dumb mistakes?” working with the hope that if we keep plugging away we will eventually discover a magic bullet. First, we need to appreciate the fact that when dealing with chronic pain there are no magic bullets. Second, we should acknowledge that our basic strategy of problem-solving, starting with the development and assessment of preclinical models right through to the design of clinical trials, hasn’t changed significantly in 20 years. When one considers that all preclinical models of chronic pain reliably produce the desired behavioral effects, and that these models have provided a much improved understanding of the putative mechanisms responsible for different pain conditions, the obvious question is “why has not all the research productivity been validated with a positive clinical outcome?” One possible answer is that for all the discoveries we have made studying pain in rodents, there seems to be little evidence of meaningful parallels with the human condition. It is also possible that what we have been studying for the past 30 years applies primarily to acute pain and that all preclinical models are distant relatives to the more clinically relevant condition of chronic pain. One cannot avoid the unthinkable possibility that we might also

Explosive overpressure brain injury (OBI) impacts the lives of both military and civilian population. We hypothesize that a single exposure to OBI results in increased hypothalamic expression of oxidative stress and activation of the sympatho-adrenal medullary axis. Since a key component of blast-induced organ injury is the primary overpressure wave, we assessed selective biochemical markers of autonomic function and oxidative stress in male Sprague Dawley rats subjected to head-directed overpressure insult. Rats were subjected to single head-directed OBI with a 358kPa peak overpressure at the target. Control rats were exposed to just noise signal being placed at ~2m distance from the shock tube nozzle. Sympathetic nervous system activation of the adrenal medullae (AM) was evaluated at 6h following blast injury by assessing the expression of catecholamine biosynthesizing enzymes, tyrosine hydroxylase (TH), dopamine-β hydroxylase (DβH), neuropeptide Y (NPY) along with plasma norepinephrine (NE). TH, DβH and NPY expression increased 20%, 25%, and 91% respectively, following OBI (P

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.Spinal Cord advance online publication, 7 February 2012; doi:10.1038/sc.2012.2.

Our objective was too assess the effectiveness of 3 analgesics (ibuprofen, naproxen sodium, and acetaminophen) and a placebo administered before and after the placement of separators in reducing the severity of postseparator placement pain. We also examined the impact of treatment on chewing efficiency at 24 hours after separator placement.Twenty-four subjects participated in the study. Each subject received 3 of 4 treatments: ibuprofen, naproxen sodium, acetaminophen, or placebo in random order at monthly intervals. The dosing times were 1 hour before separator placement and 3 and 7 hours after separator placement. Before placement, the subjects completed a masticatory efficiency test and a visual analog scale (VAS) for expected pain and pain experienced. A VAS pain diary was kept for 24 hours. Subjects returned to the clinic after 1 week for separator removal.VAS pain summary scores after separator placement were significantly affected by the administration of ibuprofen (P = 0.0298) and the time after separator placement (P0.0001). Administering ibuprofen before and after separator placement significantly reduced pain compared with the placebo. The analgesic effects diminished by day 2, resulting in peak pain levels and decreased chewing efficiency. The expected pain after separator placement also played a role in experienced pain; subjects expecting more pain experienced more pain.Ibuprofen was superior to the placebo in relieving postseparator pain as measured by the VAS pain summary scores, whereas acetaminophen and naproxen sodium did not significantly differ from the placebo.

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.

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.

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°C) when administered ip or it. Intracisternal administration of this dose produced similar results for facial stimulation (10 and 48°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.

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.

a Department of Neuroscience, College of Medicine, Comprehensive Center for Pain Research, University of Florida, 200 Newell Drive, McKnight Brain Institute, Gainesville, FL, USA b Department of Orthodontics, College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL, USA c Department of Molecular Medicine and Surgery, Section of Clinical Pain Research, Karolinska Institutet and Department of Neurosurgery, Pain Center, Karolinska University Hospital, Stockholm, Sweden

Pain in older adults is a very complex medical challenge as it often emerges with other medical conditions, which not only confounds its clinical assessment but also complicates the choices of effective treatment strategies. In this chapter, the most common types of pain-related clinical conditions in older adults will be presented. This will be followed by discussion of a number of key advances in the field of pain and aging, including in the areas of inflammation, stress, genetics and epigenetics, neuroscience, and psychosocial factors, and how advances in these key areas may help us to better assess pain in older adults as well as to devise personalized effective treatment strategies. Then, we will discuss the current choices of pain therapies, including both pharmacological and non-pharmacological treatments, along with the molecular and cellular mechanisms underlying these therapeutic approaches. At the end, we will outline a number of key future challenges and directions for pain in aging research.

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.

Pediatric spinal cord injury remains a relatively rare condition relative to its prevalence in the adult population. However, up to 5% of spinal cord injuries occur in children. In addition, age-related biomechanical and behavioral distinctions often make the detection and treatment of spine injuries in children much more challenging than in adults (1). For instance, one type of injury almost unique to children is spinal cord injury without radiographic abnormalities (SCIWORA), which by definition is more difficult to detect and therefore to treat than most adult injuries. Also, whereas neck pain is often the hallmark of spinal column injuries in adults, detecting this in a young child is a diagnostic dilemma and challenges even the most senior clinicians. Transport and management issues for the injured child also offer distinctions and challenges compared with adults. In this article, the subtleties of pediatric spinal cord injury are discussed, with a focus on the issues of diagnosis and management. EPIDEMIOLOGY

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.

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. [copy ] 2003 by the American Pain Society

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.

The condition of pain after spinal cord injury (SCI) challenges clinicians and compromises the life quality of nearly 70% of individuals with SCI. In recent years, clinical and basic science studies have provided important insights into the complexities of the psychosocial and clinical characteristics of this condition as well as mechanisms responsible for this devastating consequence of SCI. Through the use of experimental models developed to study at-level or below-level pain, there is an evolving appreciation for the mechanism(s) responsible for the onset and progression of these conditions. As a result of studies focusing on the anatomical, biochemical, molecular, and functional consequences of SCI, progress is being made in identifying therapeutic targets and designing novel strategies for the treatment of various pain conditions associated with spinal injury.

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.

Intraspinal injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS) results in excitotoxic injury which develops pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI) (R. P. Yezierski et al., 1998, Pain 75: 141–155; R. P. Yezierski et al., 1993, J. Neurotrauma 10: 445–456). Since spinal injury can lead to partial or complete deafferentation of ascending supraspinal structures, it is likely that secondary to the disruption of spinal pathways these regions could undergo significant reorganization. Recently, T. J. Morrow et al. ( Pain 75: 355–365) showed that autoradiographic estimates of regional cerebral blood flow (rCBF) can be used to simultaneously identify alterations in the activation of multiple forebrain structures responsive to noxious formalin stimulation. Accordingly, we examined whether excitotoxic SCI produced alterations in the activation of supraspinal structures using rCBF as a marker of neuronal activity. Twenty-four to 41 days after unilateral injection of QUIS into the T12 to L3 spinal segments, we found significant increases in the activation of 7 of 22 supraspinal structures examined. As compared to controls, unstimulated SCI rats exhibited a significant bilateral increase in rCBF within the arcuate nucleus (ARC), the hindlimb region of S1 cortex (HL), parietal cortex (PAR), and the thalamic posterior (PO), ventral lateral (VL), ventral posterior lateral (VPL), and ventral posterior medial (VPM) nuclei. All structures showing significantly altered rCBF are associated with the processing of somatosensory information. These changes constitute remote responses to injury and suggest that widespread functional changes occur within cortical and subcortical regions following injury to the spinal cord.

Previous studies have shown that intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Significant changes in the functional properties of sensory neurons adjacent to the site of injury have also been observed in this model. Additionally, following QUIS injections, mechanical and cold allodynia, combined with excessive grooming behavior have been shown to be the behavioral correlates of these pathological and physiological changes. These behaviors are believed to be related to the clinical conditions of spontaneous and evoked pain following SCI. Given the therapeutic properties of adrenal chromaffin cell transplantation in conditions of neuropathic and cancer pain, it is proposed that the neuroactive substances released from chromaffin cells can alter or prevent the onset and progression of QUIS-induced behavioral changes. The effects of adrenal transplants were evaluated in 14 male Long-Evans rats that received intraspinal injections of QUIS. Pain behaviors, including the progression of excessive grooming behavior (n=8) and hypersensitivity to mechanical and thermal stimuli (n=6) were evaluated following transplantation. A 53% increase in mechanical thresholds was observed following adrenal transplants along with a 70% reduction in the area of skin targeted for excessive grooming. These behaviors were not affected in 11 animals receiving transplants of skeletal muscle. The effects of adrenal transplants on cold allodynia consisted of a stabilization of response latencies in contrast to the continued decrease in latencies, i.e., increased sensitivity, following transplants of skeletal muscle. The results are consistent with previous studies showing the therapeutic efficacy of adrenal chromaffin cell transplants in neuropathic pain, and support the use of this treatment strategy for the alleviation of chronic pain following spinal cord injury.

Intraspinal injections of the AMPA-metabotropic receptor agonist quisqualic acid (QUIS) were made in an effort to simulate injury induced elevations of excitatory amino acids (EAAs), a well documented neurochemical change following spinal cord injury (SCI). The progressive pathological sequela associated with QUIS injections closely resembles the cascade of events described following ischemic and traumatic SCI and the pathogenesis of cavities in the clinical condition of post-traumatic syringomyelia. Using different injection parameters, i.e. depth and volume, to deliver QUIS into the cord the results have shown that the technique of intraspinal injection can be used to produce graded patterns of neuronal loss in specific regions of the spinal gray matter. Furthermore, neuronal loss in the dorsal horn, sparing the superficial laminae, results in the onset of spontaneous (excessive grooming behavior) and evoked (mechanical allodynia and thermal hyperalgesia) behaviors commonly associated with experimental models of chronic neuropathic pain. Thus, the present results provide a morphological correlate of spontaneous and evoked pain related behaviors following excitotoxic SCI. The behavioral characteristics combined with the similarities between QUIS induced injury and the clinical pathology of SCI support the use of the excitotoxic model in studies related to the central mechanism(s) of altered sensation, including pain, following spinal injury.

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.

A behavioral and physiological method has been developed to study thermal detection in the rat. Threshold temperatures signaling (1) disruption of a trained behavior (forelimb bar pressing) and (2) increased heart rate were determined using a gradually increasing thermal stimulus delivered to the hindlimb. Response thresholds for disruption of bar press activity (44.8 degrees C) and heart rate elevation (44.4 degrees C) were statistically equivalent. No differences in thresholds for either response end point were found between the left and right hindlimbs, thus validating the consistency of the technique and reproducibility of the stimulus delivery device during test periods of 3-4 weeks. Advantages of the method include the use of two independent end points that are determined objectively, performance criteria that do not rely upon motor responses from the stimulated limb and the use of quantitative descriptors that enables comparisons to be made between different test groups. The method combines behavior with cardiovascular and somatosensory function in a way that can be used for the assessment of spinal and supraspinal pathways involved in thermal detection in the unanesthetized, behaviorally active rat.

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.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.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.

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.Spinal Cord advance online publication, 20 December 2011; doi:10.1038/sc.2011.156.

Although cavitary lesions of the spinal cord have been recognized for centuries, only recently have effective, noninvasive imaging techniques allowed antemortem diagnosis of this clinical syndrome. Methods of treatment have not been consistently successful in alleviating or reversing the clinical symptoms caused by these cystic lesions. Incomplete understanding of the underlying pathologic basis for the syringes has impeded the development of effective methods of treatment. This review documents historical considerations regarding clinical observations and experimental studies of this entity and the animal models that have been reported for each of the major types of syringomyelia. Recent studies have suggested that development of a relevant animal model of posttraumatic syringomyelia is imminent. Successful development of an experimental model will not only permit definition of the pathogenesis of cyst formation but also provide methods for testing of therapeutic interventions.

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.

The mechanoreceptive properties of rat spinal sensory neurons were evaluated in segments adjacent to those injected with the excitatory amino acid agonist quisqualic acid. Following survival periods of 7–36 days cells recorded in quisqualate injected animals had an increased level of background activity, increased sensitivity to mechanical stimuli, and an increase in the duration of afterdischarge responses. It is suggested that a central mechanism that alters the functional state of neurons may be responsible for the sensory abnormalities, e.g. allodynia and hyperalgesia, that occur following excitotoxic induced cell death associated with ischemic and traumatic spinal cord injury.

Altered sensations, including pain, are well-documented 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 at- and 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.

The distribution of cells belonging to the rat spinomesencephalic tract was studied by means of the retrograde transport of fluorescent dyes. Bilateral midbrain injections of cytoplasmic and nuclear tracers were made in order to evaluate the location of ipsilateral, contralateral, or bilaterally projecting cells. Spinal neurons with ascending projections to midbrain and descending propriospinal projections were identified by midbrain and spinal injections of different cytoplasmic labels. The locations of spinomesencephalic tract cells included seven regions of the spinal gray matter: marginal zone, lateral neck of the dorsal horn, nucleus proprius, the region around the central canal, the lateral cervical and spinal nuclei and the ventral horn. Cells projecting to the ipsilateral or contralateral midbrain had similar distributions and were frequently found in clusters with overlapping dendritic fields. Approximately 75% of spinomesencephalic cells projected to the contralateral midbrain. The largest contribution to the spinomesencephalic tract cell population was found in cervical cord segments 1-4. Cells with bilateral projections accounted for nearly 2% of all labeled cells, whereas 5% had both ascending and descending projections. Spinomesencephalic cells were found to have varying dendritic fields and morphology, e.g. fusiform, pyramidal, round/oval, and multipolar. The results of the present study lend further support to the view that the spinomesencephalic tract is a multi-component pathway with varied origins and projection targets.

In our previous studies, psychological stress enhanced operant escape responding of male and female rats. The stressors that produced hyperalgesia were physical restraint and social defeat. Another source of stress is pain, but effects of nociceptive stimulation on pain sensitivity of laboratory animals have not been documented using a stress paradigm. Reflex responses to nociceptive stimulation are reduced by concurrent stimulation at a remote site (termed diffuse noxious inhibitory control). However, 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°C stimulation, escape responding increased during a second trial of 44.5°C stimulation (preceded by an escape trial of 10°C). Similarly, escape from cold (10°C) was enhanced when preceded by escapable 44.5°C stimulation. Thus, nociceptive stimulation enhanced subsequent escape from thermal stimulation, demonstrating facilitation of pain by pain. In contrast, an opposite profile of reflex suppression followed prior nociceptive stimulation. Reflex responses to 44.5°C were decreased following a 10°C escape trial, and reflex responses to 10°C were decreased following a 44.5°C escape trial .

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.

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.

Traumatic and/or ischemic spinal cord injury (SCI) causes local cell death and dysfunction from the primary insult and from initiation of excitotoxic and inflammatory cascades.4,10,24 SCI often causes sensory, autonomic, and motor dysfunction and loss, including at-level and below-level pain.8,38,40 Historically, SCI research has focused on the injury epicenter and adjacent tissue. Recent efforts to understand the full impact of SCI have led to studies focusing on remote sites, including cortical and subcortical regions of the brain.1,5,19 Potential effects of SCI on peripheral sensory function and tissues are not as well-characterized. Because primary afferents extend 1 of their 2 axons into the spinal cord, we investigated whether dorsal horn injury might have peripheral consequences that contribute to functional/behavioral sensory changes. A secondary goal of this study was to further investigate the anatomical substrate for dermatomal scratching after SCI. Intramedullary injection of quisqualate (QUIS) results in spontaneous biting and scratching behavior at the dermatome associated with the level of injury. This “overgrooming” or “excessive grooming” is associated with loss of neurons in the deep dorsal horn while sparing neurons in the superficial lamina.36 Elimination of neurons in this region that express NK-1 receptors prevents or eliminates excessive grooming behavior.39 Although traditionally interpreted as a manifestation of spontaneous pain,36 a recent alternative hypothesis is that overgrooming may reflect uncontrolled scratching of neuropathic itch.9 The rationale for this proposal is that patients with neuropathic pain usually shield their affected area from contact, which can be painful (allodynia), whereas patients with neuropathic scratching report that their motivation is itch, not pain.22 Patients whose neuropathic itch has led to self-injury from their scratching (like QUIS-injected rats), report that loss of pain sensation from their injury removes the natural protection that limits scratching.21 A human correlate of overgrooming in QUIS-injected rats—dermatomal itching and scratching—has been proposed in patients with SCI from intramedullary cavernous hemangiomas.9,33,41 This has been suggested to represent central itch, since these hemangiomas were intramedullary. Hemosiderin and gliosis were posited to trigger ectopic activity of second-order itch projection neurons in dorsal horn lamina I.2 The current study examines an alternative hypothesis that QUIS injection may cause damage to at-level peripheral nerves. We evaluated whether there were peripheral axonal correlates of QUIS overgrooming using computerized stereological methods to estimate total length of PGP9.5-IR axons within the epidermis. We compared skin sampled from unoperated rats and rats that did or did not overgroom after QUIS injections. More than 90% of such epidermal neurites are TRPV1-IR nociceptors.29 Additionally, the presence of activating transcription factor-3 (ATF-3) immunoreactivity in at-level dorsal root ganglia neuronal cell bodies was assessed to determine if cutaneous neurite loss after QUIS injection represents central-distal peripheral axonopathy31 or death of entire primary afferent fibers. The results suggest that intramedullary QUIS injection, a model of SCI, causes profound peripheral nervous system (PNS) as well as central nervous system (CNS) injury, and that development of post-QUIS dermatomal overgrooming, currently used as a marker of central pain, may in addition represent neuropathic itch in profoundly denervated skin.

1. The effects of electrical stimulation at different rostrocaudal levels of the midbrain, and at sites in the rostral medulla ipsilateral and contralateral to spinal recording sites, were evaluated against the responses of 46 cells belonging to the cat spinomesencephalic tract (SMT). 2. Inhibitory and/or excitatory effects of brain stem stimulation were observed on SMT cells that responded best (26 cells) or exclusively (12 cells) to noxious mechanical or thermal stimuli, as well as on 7 cells responding only to tap and/or stimulation of deep tissues. Recording sites for 32 cells were located in laminae V-VIII (27 cells) and laminae I-III (5 cells). 3. Midbrain stimulation sites were located in the superior colliculus, central gray (CG), red nucleus, and the midbrain reticular formation. Both inhibitory-only and excitatory-only effects were observed, although the most common effect of midbrain stimulation was excitation followed by inhibition (mixed effects). The effects of stimulation at different midbrain levels were determined for each cell. Stimulation in the caudal, middle, or rostral midbrain was often found to exert different effects on the same SMT cell. 4. Stimulation in the rostral medulla at sites located in nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis, and nucleus reticularis magnocellularis produced the same complement of effects observed with midbrain stimulation. Excitation followed by inhibition was the most common effect observed. 5. Stimulus intensities required to produce excitatory or inhibitory effects from midbrain were 114 +/- 85 (SD) microA and 210 +/- 91 microA, respectively. Stimulus currents required to produce excitatory or inhibitory effects from medullary stimulation sites were 124 +/- 56 microA and 70 +/- 60 microA, respectively. The mean currents required to produce mixed effects were 221 +/- 120 microA (midbrain) and 127 +/- 71 microA (medulla). Increasing the stimulus intensity used to evaluate brain stem effects increased the magnitude and duration of effects for 33 cells. Mixed effects were observed on 11 cells at stimulus intensities greater than those required to produce inhibitory-only effects. 6. Significant differences were found between the latencies of excitation and inhibition produced from different brain stem levels. These differences suggest that midbrain and medullary stimulation activate descending pathways with a wide range of conduction velocities and/or supraspinal and spinal connectivities. 7. The spinal trajectory of pathways contributing to the varied effects of brain stem stimulation as well as the complex receptive fields (RFs) of SMT cells were evaluated by the placement of lesions in the cervical spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)