Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.

The innate immune system is increasingly appreciated to play an important role in the mediation of chronic pain, and one molecule implicated in this process is the Toll-like receptor 4 (TLR4). Here, using pharmacological and genetic manipulations, we found that activating TLR4 in the spinal cord, with the agonist lipopolysaccharide (LPS), causes robust mechanical allodynia but only in male mice. Spinal LPS had no pain-producing effect in female mice. TLR4 also has a sex-specific role in inflammatory (complete Freund's adjuvant) and neuropathic (spared nerve injury) pain: pain behaviors were TLR4 dependent in males but TLR4 independent in females. The sex differences appear to be specific to the spinal cord, as LPS administered to the brain or the hindpaw produces equivalent allodynia in both sexes, and specific to pain, as intrathecal LPS produces equivalent hypothermia in both sexes. The involvement of TLR4 in pain behaviors in male mice is dependent on testosterone, as shown by gonadectomy and hormone replacement. We found no sex differences in spinal Tlr4 gene expression at baseline or after LPS, suggesting the existence of parallel spinal pain-processing circuitry in female mice not involving TLR4.

Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking) and dynamic weight bearing (gait) changes are not measures of neuropathic pain in mice.

BACKGROUND: Spontaneous (non-evoked) pain is a major clinical symptom of neuropathic syndromes, one that is understudied in basic pain research for practical reasons and because of a lack of consensus over precisely which behaviors reflect spontaneous pain in laboratory animals. It is commonly asserted that rodents experiencing pain in a hind limb exhibit hypolocomotion and decreased rearing, engage in both reflexive and organized limb directed behaviors, and avoid supporting their body weight on the affected side. Furthermore, it is assumed that the extent of these positive or negative behaviors can be used as a dependent measure of spontaneous chronic pain severity in such animals. In the present study, we tested these assumptions via blinded, systematic observation of digital video of mice with nerve injuries (chronic constriction or spared nerve injury), and automated assessment of locomotor behavior using photocell detection and dynamic weight bearing (i.e., gait) using the CatWalk system. RESULTS: We found no deficits in locomotor activity or rearing associated with neuropathic injury. The frequency of asymmetric (ipsilaterally directed) behaviors were too rare to be seriously considered as representing spontaneous pain, and in any case did not statistically exceed what was blindly observed on the contralateral hind paw and in control (sham operated and unoperated) mice. Changes in dynamic weight bearing, on the other hand, were robust and ipsilateral after spared nerve injury (but not chronic constriction injury). However, we observed timing, pharmacological, and genetic dissociation of mechanical allodynia and gait alterations. CONCLUSIONS: We conclude that spontaneous neuropathic pain in mice cannot be assessed using any of these measures, and thus caution is warranted in making such assertions.

Effects of electroconvulsive therapy on cognitive functioning in patients with depression: protocol for a systematic review and meta-analysis.

INTRODUCTION: Depression is the leading cause of disability worldwide, affecting approximately 350 million people. Evidence indicates that only 60-70% of persons with major depressive disorder who tolerate antidepressants respond to first-line drug treatment; the remainder become treatment resistant. Electroconvulsive therapy (ECT) is considered an effective therapy in persons with treatment-resistant depression. The use of ECT is controversial due to concerns about temporary cognitive impairment in the acute post-treatment period. We will conduct a meta-analysis to examine the effects of ECT on cognition in persons with depression. METHODS: This systematic review and meta-analysis has been registered with PROSPERO (registration number: CRD42014009100). We developed our methods following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We are searching MEDLINE, PsychINFO, EMBASE, CINAHL and Cochrane from the date of database inception to the end of October 2014. We are also searching the reference lists of published reviews and evidence reports for additional citations. Comparative studies (randomised controlled trials, cohort and case-control) published in English will be included in the meta-analysis. Three clinical neuropsychologists will group the cognitive tests in each included article into a set of mutually exclusive cognitive subdomains. The risk of bias of randomised controlled trials will be assessed using the Jadad scale. We will supplement the Jadad scale with additional questions based on the Cochrane risk of bias tool. The risk of bias of cohort and case-control studies will be assessed using the Newcastle-Ottawa Scale. We will employ the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess the strength of evidence. STATISTICAL ANALYSIS: Separate meta-analyses will be conducted for each ECT treatment modality and cognitive subdomain using Comprehensive Meta-Analysis V.2.0.