Jeffrey Mogil

McGill University | McGill · Alan Edwards Centre for Research on Pain (AECRP)

Chronic post-surgical pain affects a large proportion of people undergoing surgery, delaying recovery time and worsening quality of life. Although many environmental variables have been established as risk factors, less is known about genetic risk. To uncover genetic risk factors we performed genome-wide association studies in post-surgical cohorts...

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here we showed that repeated general anesthesia in postnatal mice induces preferential...

Descending control of nociception (DCN; also known as conditioned pain modulation [CPM], the behavioral correlate of diffuse noxious inhibitory controls) is the phenomenon whereby pain inhibits pain in another part of the body and is the subject of increasing study because it may represent a biomarker of chronic pain. We recently discovered that pa...

Facial grimaces are now commonly used to quantify spontaneous pain in mice and other mammalian species, but scoring remains subjective and relies on humans with very different levels of proficiency. Here, we developed a Mouse Grimace Scale (MGS) for black-coated (C57BL/6) mice consisting of four facial action units (orbitals, nose, ears, whiskers)....

Human epidemiological studies suggest that chronic pain can increase mortality risk. We investigated whether this was true in mice, so that underlying mechanisms might be identified. At 10 weeks of age, C57BL/6 mice of both sexes received sham or spared nerve injury (SNI) surgeries producing neuropathic pain. Mice were weighed monthly, tested behav...

Activation of microglia in the spinal cord dorsal horn following peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that following peripheral nerve injury, microglia degrade extracellular matrix...

In an attempt to improve reproducibility, more attention is being paid to potential sources of stress in the laboratory environment. Here, we report that the mere proximity of pregnant or lactating female mice causes olfactory-mediated stress-induced analgesia, to a variety of noxious stimuli, in gonadally intact male mice. We show that exposure to...

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability, and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activatio...

The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) and performed transcriptome-wide analysis in peripheral immune cells of 98 participants with acute LBP, followed for 3 months. Transcri...

Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve inj...

The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the environment in which events occur, were recently described as a critical regulator of pain memory; both male rodents and...

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that periphe...

The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the surrounding environment where events occur, were recently described as a critical regulator of pain memory; both rodents...

Best practices in preclinical algesiometry (pain behaviour testing) have shifted over the past decade as a result of technological advancements, the continued dearth of translational progress and the emphasis that funding institutions and journals have placed on rigour and reproducibility. Here we describe the changing trends in research methods by...

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions (COPC). Whether COPC represents a distinct pathophysiology from the occurrence of pain at only one site is unknown. Using genome-wide approaches, we compared genetic determinants of chronic single-site vs. multisite pain in the UK Biob...

Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain unknown. Here, we show that peripheral...

Pain is an immense clinical and societal challenge, and the key to understanding and treating it is variability. Robust interindividual differences are consistently observed in pain sensitivity, susceptibility to developing painful disorders, and response to analgesic manipulations. This review examines the causes of this variability, including bot...

Introduction: Mast cell (MC) activation could establish a positive feedback loop that perpetuates inflammation and maintains pain. Stabilizing MCs with ketotifen fumarate (KF) may disrupt this loop and relieve pain. Objective: We aimed to test the effect of treatment with KF in pain assays in mice and in a case series of patients with chronic wi...

Genomic and other “omic” approaches are now routinely applied to the study of pain. Some of these investigations have utilized pediatric populations. This review describes what is currently known about the heritability of pain in children (from twin studies), genes relevant to pain in children (from single-gene mutations, candidate gene, and genome...

Our understanding of how pain in early life differs to that in maturity is continuing to increase and develop, using a mixture of approaches from basic science, clinical science, and implementation science. The new edition of the Oxford Textbook of Pediatric Pain brings together an international team of experts to provide an authoritative and compr...

Background and purpose: The μ-opioid receptor (MOR) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM μ-opioid receptor (MOR) isoforms mediate inhibitory and excitatory cellular effects. Here, we developed 6TM- and 7TM-MOR selective compounds to further our understanding of the pharmacodynamic properties of MORs. Exper...

In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief o...

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unknown whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. We show, using single-cell RNA-sequencing, that nerve...

The development of new analgesic drugs has been hampered by the inability to translate preclinical findings to humans. This failure is due in part to the weak connection between commonly used pain outcome measures in rodents and the clinical symptoms of chronic pain. Most rodent studies rely on the use of experimenter-evoked measures of pain and as...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The adaptive significance of acute pain (to withdraw from tissue-damaging or potentially tissue-damaging external stimuli, and to enhance the salience of the stimulus resulting in escape and avoidance learning) and tonic pain (to enforce recuperation by punishing movement) are well-accepted [1]. Pain researchers, however, generally assert that chro...

The measurement of pain in animals is surprisingly complex, and remains a critical issue in veterinary care and biomedical research. Based on the known utility of pain measurement via facial expression in verbal and especially non-verbal human populations, “grimace scales” were first developed a decade ago for use in rodents and now exist for 10 di...

Introduction:. Increasing attention is being paid to the effects of organismic factors like age on pain sensitivity. However, very little data exist on this topic using modern algesiometric assays and measures in laboratory rodents. Objectives:. We investigated the effect of age and duration of nerve injury on baseline mechanical thresholds, neurop...

The current International Association for the Study of Pain (IASP) definition of pain as “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted...

Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as...

Despite large efforts to test analgesics in animal models, only a handful of new pain drugs have shown efficacy in patients. Here, we report a systematic review and meta-analysis of preclinical studies of the commercially successful drug pregabalin. Our primary objective was to describe design characteristics and outcomes of studies testing the eff...

The poor translational record of pain research has suggested to some observers that species differences in pain biology might be to blame. In this review, I consider the evidence for species similarity and differences in the pain research literature. Impressive feats of translation have been demonstrated in relation to certain genetic effects, soci...

Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent co-morbid sequelae of trauma that occur at different rates in women and men. We sought to identify microRNA (miRNA) that may contribute to sex-dependent differences in vulnerability to these outcomes. Monte Carlo simulations (x10,000) identified miRNA in whic...

The dorsal horn of the spinal cord is the first integration site of somatosensory inputs from the periphery. In the superficial layers of the dorsal horn, nociceptive inputs are processed by a complex network of excitatory and inhibitory interneurons whose function and connectivity remain poorly understood. We examined the role of calretinin-expres...

In the version of this Comment originally published, the authors omitted a funding source. Grant 5 P50 DA039841 (to E.J.C.) from the US National Institute on Drug Abuse has been added to the Acknowledgements in the HTML and PDF versions of the paper.

Despite continuing concern over anthroporphism, the past few decades have seen a huge increase in studies of the cognitive, emotional and social abilities of nonhuman animals. The current review focuses on research in these domains using laboratory rodents, especially rats and mice, as subjects. Evidence is accumulating that rodents are capable of...

The processing of pain in the central nervous system is now known to have an important immune component, including T cells. T cells have been shown to release endogenous opioids, and although it is well known that opioids have effects on T cell populations, very little attention has been given to the converse: how T cells may affect opioid regulati...

Sex differences in pain processing mechanisms are increasingly recognized. In our previous study, we observed that female mice, unlike males, do not require microglia to produce pain hypersensitivity after neuropathic or inflammatory injury. Using T-cell deficient mice, we found that female mutant mice “switch” to the “male” microglial system. Impo...

Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people be...

Chronic pain is a debilitating and poorly treated condition whose underlying mechanisms are poorly understood. Nerve injury and inflammation cause alterations in gene expression in tissues associated with pain processing, supporting molecular and cellular mechanisms that maintain painful states. However, it is not known whether transcriptome change...

The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyper...

Inbred mice are preferred over outbred mice because it is assumed that they display less trait variability. We compared coefficients of variation and did not find evidence of greater trait stability in inbred mice. We conclude that contrary to conventional wisdom, outbred mice might be better subjects for most biomedical research.

Importance After a drug receives regulatory approval, researchers often pursue small, underpowered trials, called exploratory trials, aimed at testing additional indications. If favorable early findings from exploratory trials are not promptly followed by confirmatory trials, then physicians, patients, and payers can be left uncertain about a drug’...

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide ass...

Whether there are sex differences in pain sensitivity is a topic of enduring interest. This question has essentially been answered, with a clear consensus emerging in the direction of the difference in humans. More importantly, though, there is also much evidence for robust qualitative differences in pain mechanisms between the sexes, in both roden...

Dorsal root ganglion (DRG) neurons provide connectivity between peripheral tissues and spinal cord. Transcriptional plasticity within DRG sensory neurons after peripheral nerve injury contributes to nerve repair but also leads to maladaptive plasticity, including the development of neuropathic pain. This study presents tissue and neuron specific ex...

The processing of pain in the central nervous system is now known to have an important immune component, including T cells of the adaptive immune system. T cells have been shown to release endogenous opioids, and although it is well known that opioids have effects on T cell populations, very little attention has been given to the converse: how T ce...

The potential influence of pain on social behavior in laboratory animals has rarely been evaluated. Using a new assay of social behavior, the tube co‐occupancy test (TCOT), we assess propinquity—the tendency to maintain close physical proximity—in mice exposed to pain using subcutaneous zymosan or spared nerve injury as noxious stimuli. Our previou...

The Oxford Handbook of the Neurobiology of Pain represents a state of the art overview of the rapidly developing field of pain research. As populations age, the number of people in pain is growing dramatically, with half the population living with pain. The opioid crisis has highlighted this problem. The present volume is thus very timely, providin...

Chronic pain is a pathological condition characterized by long-lasting pain after damaged tissue has healed. Chronic pain can be caused and maintained by changes in various components of the pain pathway, including sensory neurons, spinal cord and higher brain centers. Exaggerated sensitivity and responsiveness of spinal nociceptive circuits, repre...

Acute pain serves as a protective mechanism, guiding the organism away from actual or potential tissue injury. In contrast, chronic pain is a debilitating condition without any obvious physiological function. The transition to, and the maintenance of chronic pain require new gene expression to support biochemical and structural changes within the p...

Microglia-neuron signalling in the spinal cord is a key mediator of mechanical allodynia caused by peripheral nerve injury. We recently reported sex differences in microglia in pain signalling in mice: spinal mechanisms underlying nerve injury-induced allodynia are microglial dependent in male but not female mice. Whether this sex difference in pai...

Grimace scales quantify characteristic facial expressions associated with spontaneous pain in rodents and other mammals. However, these scales have not been widely adopted largely because of the time and effort required for highly trained humans to manually score the images. Convoluted neural networks were recently developed that distinguish indivi...

Objective: To outline the role that spontaneous osteoarthritis in companion animals can play in translational research and therapeutic pharmacological development. Outline: Narrative review summarizing the opportunities and limitations of naturally occurring, spontaneous osteoarthritis as models of human osteoarthritis pain, with a focus on comp...

It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in c...

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGF...

Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryot...

Failure of analgesic drugs in clinical development is common. Along with the current "reproducibility crisis" in pain research, this has led some to question the use of animal models. Experimental models tend to comprise genetically homogeneous groups of young, male rodents in restricted and unvarying environments, and pain-producing assays that ma...

Significance We developed an assay of social behavior, the tube cooccupancy test. This assay is able to identify deficits in social behavior of known “autistic-like” mouse strains. Using the test, we revealed a major difference in social behavior between inbred and outbred strains, with only the latter behaving similar to wild mice.

Graphical Abstract Highlights d Expression quantitative trait loci (eQTLs) are mapped in a collection of human DRGs d Pain-related genetic association results can be explained by DRG eQTLs d eQTLs predict contribution of the human leukocyte antigen locus to pain phenotypes d The dataset is a tool for interpretation of human GWAS with a sensory comp...

The poor record of basic-to-clinical translation in recent decades has led to speculation that preclinical research is “irreproducible”, and this irreproducibility in turn has largely been attributed to deficiencies in reporting and statistical practices. There are, however, a number of other reasonable explanations of both poor translation and dif...

Jeffrey S. Mogil and Malcolm R. Macleod propose a new kind of paper that combines t