Evidence that increased cholecystokinin (CCK) in the periaqueductal gray (PAG) facilitates changes in Resident-Intruder social interactions triggered by peripheral nerve injury.

Individual differences in the effects of a chronic neuropathic injury on social behaviours characterize both the human experience and pre-clinical animal models. The impacts of these changes to the well-being of the individual are often underappreciated. Earlier work from our laboratory using GeneChip® microarrays identified increased cholecystokinin (CCK) gene expression in the periaqueductal gray (PAG) of rats that showed persistent changes in social interactions during a Resident-Intruder encounter following sciatic nerve chronic constriction injury (CCI). In this study, we confirmed these gene regulation patterns using RT-PCR and identified the anatomical location of the CCK-mRNA as well as the translated CCK peptides in the midbrains of rats with a CCI. We found that rats with persistent CCI-induced changes in social behaviours had increased CCK-mRNA in neurons of the ventrolateral PAG and dorsal raphe nuclei, as well as increased CCK-8 peptide expression in terminal boutons located in the lateral and ventrolateral PAG. The functional significance of these changes was explored by microinjecting small volumes of CCK-8 into the PAG of uninjured rats and observing their Resident-Intruder social interactions. Disturbances to social interactions identical to those observed in CCI rats were evoked when injection sites were located in the rostral lateral and ventrolateral PAG. We suggest that CCI-induced changes in CCK expression in these PAG regions contributes to the disruptions to social behaviours experienced by a subset of individuals with neuropathic injury.

Psychometric Evaluation of the Brachial Assessment Tool Part 1: Reproducibility.

OBJECTIVE: To evaluate reproducibility (reliability and agreement) of the Brachial Assessment Tool (BrAT), a new patient-reported outcome measure for adults with traumatic brachial plexus injury (BPI). DESIGN: Prospective repeated-measure design. SETTING: Outpatient clinics. PARTICIPANTS: Adults with confirmed traumatic BPI (N=43; age range, 19-82y). INTERVENTIONS: People with BPI completed the 31-item 4-response BrAT twice, 2 weeks apart. Results for the 3 subscales and summed score were compared at time 1 and time 2 to determine reliability, including systematic differences using paired t tests, test retest using intraclass correlation coefficient model 1,1 (ICC1,1), and internal consistency using Cronbach α. Agreement parameters included standard error of measurement, minimal detectable change, and limits of agreement. MAIN OUTCOME MEASURE: BrAT. RESULTS: Test-retest reliability was excellent (ICC1,1=.90-.97). Internal consistency was high (Cronbach α=.90-.98). Measurement error was relatively low (standard error of measurement range, 3.1-8.8). A change of >4 for subscale 1, >6 for subscale 2, >4 for subscale 3, and >10 for the summed score is indicative of change over and above measurement error. Limits of agreement ranged from ±4.4 (subscale 3) to 11.61 (summed score). CONCLUSIONS: These findings support the use of the BrAT as a reproducible patient-reported outcome measure for adults with traumatic BPI with evidence of appropriate reliability and agreement for both individual and group comparisons. Further psychometric testing is required to establish the construct validity and responsiveness of the BrAT.

Preliminary Psychometric Evaluation of the Brachial Assessment Tool Part 2: Construct Validity and Responsiveness.

OBJECTIVES: To evaluate construct validity and responsiveness of the Brachial Assessment Tool (BrAT), a new patient-reported outcome measure for people with traumatic brachial plexus injury (BPI), and to compare it to the Disabilities of the Arm, Shoulder and Hand (DASH) and the Upper Extremity Functional Index (UEFI). DESIGN: Cross-sectional study. SETTING: Outpatient clinics. PARTICIPANTS: Adults (N=29; age range, 20-69y) with confirmed traumatic BPI. INTERVENTIONS: Participants completed the BrAT 3 times over an 18-month period together with 16 DASH activity items and the UEFI. Evaluations were undertaken of construct validity, known-groups validity, 1-way repeated analysis of variance, and effect size. MAIN OUTCOME MEASURES: BrAT, DASH, and UEFI. RESULTS: The BrAT demonstrated a moderate to low correlation with the DASH activity items (<0.7) and a large correlation with the UEFI (>0.7). According to known-groups validity, only the BrAT was able to discriminate between people who stated they could use their hand versus those who were unable to use their hand to perform activities. All measures indicated a significant effect for time with the exception of BrAT subscale 1. The effect size was highest for the BrAT but lower than expected (BrAT, .52-.40; DASH, .15; UEFI, .36). CONCLUSIONS: These preliminary findings support the BrAT as a valid and responsive patient-reported outcome measure for adults with traumatic BPI. The BrAT activity items appear to be more targeted than the DASH or UEFI particularly for people with more severe BPI. The BrAT also appears to be measuring a different activity construct than the DASH and the UEFI. Further work is required to confirm these results with larger sample sizes.

Patients' views on early sensory relearning following nerve repair-a Q-methodology study.

STUDY DESIGN: Descriptive study. INTRODUCTION: Early sensory relearning where the dynamic capacity of the brain is used has been shown to improve sensory outcome after nerve repair. However, no previous studies have examined how patients experience early sensory relearning. PURPOSE OF THE STUDY: To describe patient's views on early sensory relearning. METHODS: Statements' scores were analyzed by factor analysis. RESULTS: Thirty-seven consecutive adult patients with median and/or ulnar nerve repair who completed early sensory relearning were included. Three factors were identified, explaining 45% of the variance: (1) "Believe sensory relearning is meaningful, manage to get an illusion of touch and complete the sensory relearning"; (2) "Do not get an illusion of touch easily and need support in their sensory relearning" (3) "Are not motivated, manage to get an illusion of touch but do not complete sensory relearning". DISCUSSION: Many patients succeed in implementing their sensory relearning. However, a substantial part of the patient population need more support, have difficulties to create illusion of touch, and lack motivation to complete the sensory relearning. To enhance motivation and meaningfulness by relating the training clearly to everyday occupations and to the patient's life situation is a suggested way to proceed. CONCLUSION: The three unique factors indicate motivation and sense of meaningfulness as key components which should be taken into consideration in developing programs for person-centered early sensory relearning. LEVEL OF EVIDENCE: 3.

[Damage to subcutaneous nerves in endovenous laser coagulation of the great saphenous vein]. / Povrezhdenie podkozhnykh nervov pri éndovenoznoi lazernoi koaguliatsii bol'shoi podkozhnoi veny.

The purpose of this study was to assess the incidence of the development of symptoms of damage to subcutaneous nerves after endovenous laser coagulation (EVLC) of the great saphenous vein (GSV), as well as to determine the effect of these symptoms on quality of life (QoL) of patients. Our retrospective study enrolled a total of 119 patients (mean age 50±13.9 years) subjected to 151 isolated EVLC of the GSV. The average volume of the injected anaesthetic per 1 cm of the vein's length amounted to 8.5±1.9 ml. Puncture of the GSV at the level of the thigh was performed in 37 (24.5%) cases, at the level of the crus in 114 (75.5%) cases. The intervention was performed at the power 5-10 W and linear density of energy approximately 70 J/cm. The median of the follow up period amounted to 264 days. The patients were interrogated by phone. The questionnaire included leading, understandable for patients questions about the presence of postoperative complaints characteristic of damage to subcutaneous nerves, as well as the question about the effect of these complaints on quality of life. The complaints characteristic of damage to subcutaneous nerves were reported for 61 (40.4%) operated limbs, with these symptoms decreasing quality of life only in 7 (4.6%) cases. All respondents noted gradual regression of the symptoms with time. The median of symptom relief amounted to 2 months. The analysis of interrelationship between the level of puncture by the thirds of the femur and crus and the damage of subcutaneous nerves demonstrated no statistically significant association (p=0.108), unlike the analysis by the femur/crus level, wherein the infragenicular puncture significantly increased the risk of traumatisation of subcutaneous nerves (p=0.022). No statistically significant differences by the frequency of damage to subcutaneous nerves depending on the power of energy were revealed (p=0.662). The obtained findings make it possible to recommend EVLC, including with puncture of the GSV below the knee, for patients with varicose veins in this basin.

Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain.

Affective and cognitive processing of nociception contributes to the development of chronic pain and vice versa, pain may precipitate psychopathologic symptoms. We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans. Young naïve progranulin deficient mice behaved normal in tests of short-term memory, anxiety, depression and nociception, but after peripheral nerve injury, they showed attention-deficit and depression-like behavior, over-activity, loss of shelter-seeking, reduced impulse control and compulsive feeding behavior, which did not occur in equally injured controls. Hence, only the interaction of 'pain x progranulin deficiency' resulted in the complex phenotype at young age, but neither pain nor progranulin deficiency alone. A deep proteome analysis of the prefrontal cortex and olfactory bulb revealed progranulin-dependent alterations of proteins involved in synaptic transport, including neurotransmitter transporters of the solute carrier superfamily. In particular, progranulin deficiency was associated with a deficiency of nuclear and synaptic zinc transporters (ZnT9/Slc30a9; ZnT3/Slc30a3) with low plasma zinc. Dietary zinc supplementation partly normalized the attention deficit of progranulin-deficient mice, which was in part reminiscent of autism-like and compulsive behavior of synaptic zinc transporter Znt3-knockout mice. Hence, the molecular studies point to defective zinc transport possibly contributing to progranulin-deficiency-associated psychopathology. Translated to humans, our data suggest that neuropathic pain may precipitate cognitive and psychopathological symptoms of an inherent, still silent neurodegenerative disease.

Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats.

BACKGROUND: Noxious stimulus-induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system. METHODS: We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin. RESULTS: NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005). CONCLUSIONS: These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

Obstacles to the Care of Patients With Multicomponent Volar Wrist Lacerations at a County Hospital.

BACKGROUND: Multicomponent volar wrist lacerations of "spaghetti wrist" injuries are devastating injuries of the upper extremity. These patients require long-term commitment to rehabilitation. Patients presenting to our county hospital represent a unique and complex patient population in terms of psychosocial considerations. We aimed to identify obstacles to care and optimal recovery in this patient population. METHODS: A patient database was queried for ICD-9 codes related to major upper extremity nerve injuries, which were treated by plastic surgery faculty at San Francisco General Hospital from 2008 to 2014. A retrospective chart review was performed to identify patients with spaghetti wrist injuries. Charts were reviewed for patient demographics including age, occupation, handedness, psychiatric illness, isolated versus polytrauma, and employment status. Injuries were categorized for mechanism of injury, structures involved, and timing and method of surgical treatment. Outcomes were assessed for motor recovery, sensory recovery, and tendon function. RESULTS: We identified 18 patients with multicomponent volar wrist lacerations. Average patient age was 31 years. The most common mechanism of injury was accidental/work-related (n = 9, 50%), followed by self-inflicted (n = 4, 22%). Thirty-nine percent (n = 7) of patients had a psychiatric diagnosis, most commonly depression (n = 4, 22%). Eighty-nine percent (n = 16) of patients had an isolated injury to the upper extremity, and 39% (n = 7) had an injury to the dominant hand. Fifty percent (n = 9) of patients were lost to follow-up, with 28% (n = 5) having no known care plan. Motor, sensory, and tendon function outcomes for those with adequate follow-up were comparable to previously published studies. DISCUSSION: Multicomponent volar wrist lacerations can be devastating, and although we are able to provide patients with appropriate timely surgical care, these patients require long-term care far beyond the operating room for optimal outcomes. Psychiatric illness, socioeconomic limitations, poor patient compliance, and irregular follow-up are obstacles to care. These issues highlight the need for better social support systems and mental health care to provide access to the services necessary to optimize recovery.

Effects on Spatial Cognition and Nociceptive Behavior Following Peripheral Nerve Injury in Rats with Lesion of the Striatal Marginal Division Induced by Kainic Acid.

Neuropathic pain and cognitive deficit are frequently comorbidity in clinical, but their underlying correlation and mechanisms remain unclear. Here, we utilized a combined rat model including kainic acid (KA) injection into bilateral striatal marginal division and chronic constriction nerve injury (CCI). PET/CT scans revealed that the SUVmax of KA rats was significantly decreased when compared to naive and saline rats. In contrast to the naive and saline rats, KA rats had longer latencies in locating the hidden platform on day 4, 5 in Morris water maze task. Thermal hyperalgesia and mechanical allodynia of KA rats were alleviated following CCI. Immunostaining results showed that substance P was markedly increased within ipsilateral spinal cord dorsal horn of KA rats after CCI, especially on the post-operative day 14. By means of real-time PCR, the up-regulation of GluR within ipsilateral spinal cord dorsal horn was observed in all KA and CCI rats. PKCγ, IL-6 and NF-κB were up-regulated in both CCI rats when compared to naive and their respective sham rats. These results suggest that cognitive impairment of rats altered the pain behaviors, and these intracellular regulators play crucial roles in the process of neuropathic pain.

Factors related to the psychosocial functioning of youth with neonatal brachial plexus injuries.

OBJECTIVE: Owing to the possible visible nature and functional impairments associated with neonatal brachial plexus injuries (NBPI), the current study investigated the relations of injury severity, social support, and coping strategies to social difficulties and self-concept in youth with NBPI. METHODS: 88 children (aged 10-17 years) with NBPI and their parent(s) were recruited from a national organization and two brachial plexus clinics. Participants completed a variety of questionnaires during their scheduled clinic visits. RESULTS: More social support from classmates was associated with better self-concept and fewer social difficulties. Less frequent use of negative coping strategies was associated with better self-concept and fewer social difficulties and was a significant moderator of the relation between injury severity and self-concept. CONCLUSIONS: Clinicians who work with children with NBPI should consider peer support and coping strategies when promoting the psychosocial functioning of these youth.

Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats.

Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.

Knowledge, attitudes, and practices of healthcare professionals toward rehabilitation of peripheral nerve injury.

Peripheral nerve injury (PNI) occurs due to damage of peripheral nerves, with healthcare professionals playing significant roles in PNI rehabilitation. This study aimed to explore the knowledge, attitudes, and practices (KAP) towards PNI rehabilitation among healthcare professionals. This cross-sectional study was conducted on June 2023 in China and healthcare professionals were enrolled. A total of 611 valid questionnaires were collected, with 62.52% female respondents. Mean scores for KAP were 14.26 ± 2.044 (possible range: 0-19), 29.77 ± 3.622 (possible range: 7-35), and 41.55 ± 9.523 (possible range: 11-55), respectively. Multivariate logistic regression revealed positive associations of professional titles (OR = 1.743, 95% CI: 1.083-2.804), occupation (OR = 1.833, 95% CI: 1.151-2.919), and involvement in treatment or care of PNI patients (OR = 1.462, 95% CI: 1.024-2.088) with knowledge. Knowledge (OR = 1.155, 95% CI: 1.042-1.280), gender (OR = 2.140, 95% CI: 1.255-3.646), education (OR = 2.258, 95% CI: 1.131-4.507), and involvement in treatment or care of PNI patients (OR = 2.463, 95% CI: 1.460-4.155) were positively associated with attitude. Attitude (OR = 1.214, 95% CI: 1.148-1.283), bachelor's degree education (OR = 0.548, 95% CI: 0.326-0.919), master's degree or higher (OR = 0.545, 95% CI: 0.308-0.964), having rehabilitation training for PNI (OR = 2.485, 95% CI: 1.633-3.781), and involvement in treatment or care of PNI patients (OR = 2.093, 95% CI: 1.395-3.138) were independently associated with practice. Healthcare professionals exhibited moderate knowledge, positive attitudes, and moderate practices towards the PNI rehabilitation. Those involved in the treatment or care of PNI have significantly higher KAP. Targeted interventions were needed to enhance understanding and promote proactive engagement in clinical practice.

Nociceptive, emotional, electrophysiological, and histological characterization of the chronic constriction injury model in female Wistar Han rats.

Chronic neuropathic pain affects 7-10 % of the population and is often accompanied by comorbid emotional disorders, which greatly reduce the quality of life of the patients, impairing physical, cognitive, emotional, and social functioning. Despite the higher prevalence and severity of chronic pain in women, the number of publications using female animals remains scarce. While in the chronic constriction injury (CCI) model the development of mechanical/thermal hyperalgesia, allodynia and spontaneous pain has been shown in both sexes, little is known on CCI-induced emotional impairments and sciatic nerve histopathology in female rats, as well as on the contributions of ovarian hormones to peripheral nerve injury. In this work, young adult rats (Wistar Han) were assigned to one of five groups: gonadally intact females (SHAM/SHAM), ovariectomized females (SHAM/OVX), gonadally intact females with CCI (CCI/SHAM); ovariectomized females with CCI (CCI/OVX) and males with CCI (CCIM). In the postoperative period, CCI animals, both females and males, displayed visible gait abnormalities, limping and guarding the affected hind paw although locomotion was not affected. Neuropathic females developed sustained mechanical allodynia, with CCI/OVX animals displaying symptoms two weeks before CCI/SHAM females. Interestingly, regarding mechanical and cold allodynia, CCI males slowly recovered from week 3 onwards. While CCI induced neither anxiety- nor depressive-like behaviour in females, ovariectomy per se induced anhedonic-like behaviour, regardless of CCI surgery. Histopathological analysis of the sciatic nerve showed CCI induced nerve damage, fibrosis, myelin sheath degradation and inflammation. Single-cell electrophysiological data from the rostral ventromedial medulla (RVM) suggests this area is partly involved in descending facilitation associated with experimental neuropathic pain. Altogether, our findings demonstrate CCI females display distinct sensory, emotional, electrophysiological, and histopathological impairments from males, and that ovariectomy aggravates females' responses to peripheral nerve injury.

Inhibition of plasminogen/plasmin system retrieves endogenous nerve growth factor and adaptive spinal synaptic plasticity following peripheral nerve injury.

Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders. Tissue plasminogen activator (tPA)/plasminogen (PA)/plasmin system has been involved in either process of maturation and degradation of nerve growth factor (NGF), highlighting multiple potential targets for new therapeutic strategies. We here investigated the role of intrathecal (i.t.) delivery of neuroserpin (NS), an endogenous inhibitor of plasminogen activators, on neuropathic behavior and maladaptive synaptic plasticity in the rat spinal cord following spared nerve injury (SNI) of the sciatic nerve. We demonstrated that SNI reduced spinal NGF expression, induced spinal reactive gliosis, altering the expression of glial and neuronal glutamate and GABA transporters, reduced glutathione (GSH) levels and is associated to neuropathic behavior. Beside the increase of NGF expression, i.t. NS administration reduced reactive gliosis, restored synaptic homeostasis, GSH levels and reduced neuropathic behavior. Our results hereby highlight the essential role of tPA/PA system in the synaptic homeostasis and mechanisms of maladaptive plasticity, sustaining the beneficial effects of NGF-based approach in neurological disorders.

The association between injury severity and psychological morbidity, hand function, and return to work in traumatic hand injury with major nerve involvement: A one-year follow-up study.

BACKGROUND: We aimed to investigate the association between the severity of the injury and psychological morbidities, hand functions, and return to work (RTW) in traumatic hand injury (THI) with major nerve involvement. METHODS: Thirty-two patients had THI with major nerve involvement were enrolled in this study. The demographic and clinical characteristics of the patients were recorded after the injury. The severity of the injury was evaluated using the modified Hand Injury Severity Score (MHISS). The Disabilities of the Arm, Shoulder, and Hand (Q-DASH) score and Duruöz Hand Index (DHI) were used to assess the hand function. Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Impact of Event Scale-Revised (IES) were performed to assess psychological morbidity. These assessments were performed after injury and at the end of the first year. Time to RTW was recorded in the first year after the injury. Jamar Hand Dynamometer and pinch meter were used for the measurement of hand and finger grip strength at the end of the first year. RESULTS: There were significant improvements in IES-R, BDI, BAI, Q-DASH, and DHI scores at the end of the first year compared with baseline scores. We found a significant correlation between MHISS and time of RTW, Q-DASH, and pinch strengths. We found no significant correlation between MHISS and IES-R, BDI, BAI, and grip strength. CONCLUSION: The severity of the injury is significantly associated with hand functions, pinch strengths, and RTW in THIs with major nerve involvement. The findings showed that there was no association between the severity of the injury and psychological morbidities in the present study.

Repeated exposure of naïve and peripheral nerve-injured mice to a snake as an experimental model of post-traumatic stress disorder and its co-morbidity with neuropathic pain.

Confrontation of rodents by natural predators provides a number of advantages as a model for traumatic or stressful experience. Using this approach, one of the aims of this study was to investigate a model for the study of post-traumatic stress disorder (PTSD)-related behaviour in mice. Moreover, because PTSD can facilitate the establishment of chronic pain (CP), and in the same way, patients with CP have an increased tendency to develop PTSD when exposed to a traumatic event, our second aim was to analyse whether this comorbidity can be verified in the new paradigm. C57BL/6 male mice underwent chronic constriction injury of the sciatic nerve (CCI), a model of neuropathic CP, or not (sham groups) and were submitted to different threatening situations. Threatened mice exhibited enhanced defensive behaviours, as well as significantly enhanced risk assessment and escape behaviours during context reexposure. Previous snake exposure reduced open-arm time in the elevated plus-maze test, suggesting an increase in anxiety levels. Sham mice showed fear-induced antinociception immediately after a second exposure to the snake, but 1 week later, they exhibited allodynia, suggesting that multiple exposures to the snake led to increased nociceptive responses. Moreover, after reexposure to the aversive environment, allodynia was maintained. CCI alone produced intense allodynia, which was unaltered by exposure to either the snake stimuli or reexposure to the experimental context. Together, these results specifically parallel the behavioural symptoms of PTSD, suggesting that the snake/exuvia/reexposure procedure may constitute a useful animal model to study PTSD.

A neuronal circuit for activating descending modulation of neuropathic pain.

Neuropathic pain can be a debilitating condition with both sensory and affective components, the underlying brain circuitry of which remains poorly understood. In the present study, a basolateral amygdala (BLA)-prefrontal cortex (PFC)-periaqueductal gray (PAG)-spinal cord pathway was identified that is critical for the development of mechanical and thermal hypersensitivity after peripheral nerve injury. It was shown that nerve injury strengthens synaptic input from the BLA onto inhibitory interneurons located in the prelimbic medial PFC, by virtue of reduced endocannabinoid modulation. These augmented synaptic connections mediate a feedforward inhibition of projections from the PFC to the ventrolateral PAG region and its downstream targets. Optogenetic approaches combined with in vivo pharmacology reveal that these BLA-PFC-PAG connections alter pain behaviors by reducing descending noradrenergic and serotoninergic modulation of spinal pain signals. Thus, a long-range brain circuit was identified that is crucial for pain processing and that can potentially be exploited toward targeting neuropathic pain.

Amygdaloid administration of tetrapentylammonium attenuates development of pain and anxiety-like behavior following peripheral nerve injury.

BACKGROUND: The central amygdaloid nucleus (CeA) is involved in processing and descending regulation of pain. Amygdaloid mechanisms underlying pain processing and control are poorly known. Here we tested the hypothesis that perioperative CeA administration of tetrapentylammonium (TPA), a non-selective THIK-1 channel blocker and thereby inhibitor of microglia, attenuates development of chronic neuropathic pain and comorbid anxiety-like behavior. METHODS: Rats with a spared nerve injury (SNI) model of neuropathy or sham operation had a chronic cannula for drug microinjections into the CeA or a control injection site. Monofilament test was used to evaluate pain, and light-dark box (LDB) to assess anxiety. RESULTS: Perioperative CeA treatment with TPA (30 µg/day up to the third postoperative day, D3) significantly attenuated the development of pain and anxiety-like behavior. In the late phase (> D14), CeA administration of TPA (3-30 µg) failed to influence pain. Perioperative minocycline (microglia inhibitor; 25 µg), MK-801 (an N-Methyl-D-aspartate receptor antagonist; 0.1 µg), vehicle or TPA in a control injection site failed to attenuate pain development. CONCLUSIONS: Perioperative treatment of the CeA with TPA delayed development of neuropathic pain and comorbid anxiety-like behavior, while TPA treatment failed to influence maintenance of established neuropathic pain. The failures to attenuate pain development with CeA administrations of minocycline or MK-801 do not support the hypothesis that the TPA-induced prophylactic effect was due to inhibition of amygdaloid microglia or N-methyl-D-aspartate receptors. While TPA in the CeA proved to have a prophylactic effect on SNI-induced pain behavior, the underlying mechanism still remains to be studied.

Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats.

Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.

Glial-cytokine-neuronal Adaptations in the Ventral Hippocampus of Rats with Affective Behavioral Changes Following Peripheral Nerve Injury.

Nerve damage leads to the development of disabling neuropathic pain in susceptible individuals, where patients present with pain as well as co-morbid behavioral changes, such as anhedonia, decreased motivation and depression. In this study we evaluated whether radial maze behavioral disruptions and glia-cytokine-neuronal adaptations in the hippocampus occurred in individual rats after nerve injury. Exploration behavior and spatial memory were quantified using a radial maze task, while mechanical allodynia was assessed using von Frey testing. Sciatic nerve chronic constriction injury (CCI) reduced withdrawal thresholds in all rats, while pellet-seeking behaviors were altered in some but not all rats. One group, termed 'No effect', had no behavioral changes compared to sham rats. Another group, termed 'Acute effect', had a temporary alteration to their exploration pattern, displaying more risk-assessment behavior in the early phase post-injury. In a third group, termed 'Lasting effect', exploratory behaviors were remarkably different for the entire post-injury period, showing a withdrawal from pellet-seeking. The withdrawal from pellet-seeking was found to be concomitant with distinct glial-cytokine-neuronal adaptations within the contralateral ventral hippocampus, including; increased expression of IL-1ß and MCP-1; astrocyte atrophy and decreased area in the dentate gyrus; reactive microglia and increased FosB/ΔFosB expression in the cornu ammonis subfield. Therefore, glial-cytokine-neuronal adaptations in the ventral hippocampus may mediate individual differences in radial maze behavior following CCI. Our data suggest that individual neuroimmune signatures play a significant role in divergent behavioral trajectories following nerve injury, toward functional recovery and coping, or the emergence of ongoing affective state disturbances.