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Jeffrey S Mogil

Publications and source records attributed to Jeffrey S Mogil.

At least 19 recordsLinked to original sources
PubMed2024

Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain.

BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.

Animals↗
PubMed2006

Screening for pain phenotypes: analysis of three congenic mouse strains on a battery of nine nociceptive assays.

In an attempt to identify new genes responsible for variability in pain sensitivity, we tested three congenic mouse strains--in which a small portion of the genome of the MOLF/Ei strain has been placed on a C57BL/6 genetic background--on a battery of nine nociceptive assays, chosen to reflect those assays in most common use in the pain literature. Mice of both sexes were evaluated by two different testers at different points in time, allowing us to examine the relative importance of genotype, sex, tester and cohort effects on data from these assays. We find strong evidence for the existence of two quantitative trait loci (i.e., genomic regions containing variability-causing genes), one for thermal nociception on mouse chromosome (Chr) 17 (Chr 17; Tpnr3) and one for formalin test nociception on mouse Chr 12 (Nociq3). We note, however, that the nociceptive assays in this battery feature strong main effects and interactions of sex, tester, and cohort, which if not controlled or covaried can seriously confound interpretation of genetic experiments, including the comparison of transgenic knockout mice to their wild-type controls.

Animals↗
PubMed2006

Social modulation of pain as evidence for empathy in mice.

Empathy is thought to be unique to higher primates, possibly to humans alone. We report the modulation of pain sensitivity in mice produced solely by exposure to their cagemates, but not to strangers, in pain. Mice tested in dyads and given an identical noxious stimulus displayed increased pain behaviors with statistically greater co-occurrence, effects dependent on visual observation. When familiar mice were given noxious stimuli of different intensities, their pain behavior was influenced by their neighbor's status bidirectionally. Finally, observation of a cagemate in pain altered pain sensitivity of an entirely different modality, suggesting that nociceptive mechanisms in general are sensitized.

Altruism↗
PubMed2006

Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse.

Itch features considerable interindividual variability in humans, and initial studies using animal models have demonstrated a likely role of genetic factors in mediating such variability. In an attempt to systematically study genetic mediation of itch in the mouse such that gene identification by linkage mapping might be achieved, we examined scratching behavior induced by histamine and chloroquine in mice of 11 inbred mouse strains. Multiple chloroquine drug doses were used, revealing the existence of inverted-U dose-response relationships in every strain, allowing us to determine strain-dependent peak scratching behavior over the entire dose range. Peak chloroquine-induced scratching varied by 2.5-fold in this set of strains; scratching behavior shows moderate heritability in the mouse. The present data also reveal, for the first time, significant sex differences in pruritogen-induced scratching behavior, with female mice scratching an average of 23% more than males. Finally, a comparison of the strain means obtained here with previously collected data using nociceptive assays revealed a suggestive negative genetic correlation between chloroquine-induced itch and thermal pain, such that strains sensitive to pain are resistant to itch and vice versa. This finding may have implications both for our understanding of itch pathophysiology and for the identification of itch-related genes.

Analysis of Variance↗
PubMed2006

Sex differences in the effects of amiloride on formalin test nociception in mice.

Amiloride is a nonspecific blocker of acid-sensing ion channels (ASICs) that have been recently implicated in the mediation of mechanical and chemical/inflammatory nociception. Preliminary data using a transgenic model are suggestive of sex differences in the role of ASICs. We report here that systemic administration of amiloride (10-70 mg/kg ip) produces a robust, dose-dependent blockade of late/tonic phase nociceptive behavior on the mouse formalin test (5%; 20 microl) in female but not male mice, completely abolishing the known sex difference in formalin test response. Adult gonadectomy produced a "switching" of sex differences in amiloride efficacy, with castrated males displaying an amiloride blockade and ovariectomized females rendered less sensitive to amiloride. Gonadectomized mice could be switched back to their intact status using chronic estrogen benzoate or testosterone propionate replacement via osmotic minipump (6 microg/day or 250 microg/day, respectively). It is unclear whether this striking sex difference is due to sex-specific involvement of ASICs in pain processing, but the present data represent one of the first demonstrations of pain-related sex differences with no obvious opioid involvement.

Amiloride↗
PubMed2005

Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli.

Molecular and behavioral evidence suggests that acid-sensing ion channels (ASICs) contribute to pain processing, but an understanding of their precise role remains elusive. Existing ASIC knock-out mouse experiments are complicated by the heteromultimerization of ASIC subunits. Therefore, we have generated transgenic mice that express a dominant-negative form of the ASIC3 subunit that inactivates all native neuronal ASIC-like currents by oligomerization. Using whole-cell patch-clamp recordings, we examined the response properties of acutely isolated dorsal root ganglion neurons to protons (pH 5.0). We found that whereas 33% of the proton-responsive neurons from wild-type mice exhibited an ASIC-like transient response, none of the neurons from the transgenic mice exhibited a transient inward current. Capsaicin-evoked responses mediated by the TRPV1 receptor were unaltered in transgenic mice. Adult male wild-type and transgenic mice were subjected to a battery of behavioral nociceptive assays, including tests of thermal, mechanical, chemical/inflammatory, and muscle pain. The two genotypes were equally sensitive to thermal pain and to thermal hypersensitivity after inflammation. Compared with wild types, however, transgenic mice were more sensitive to a number of modalities, including mechanical pain (von Frey test, tail-clip test), chemical/inflammatory pain (formalin test, 0.6% acetic acid writhing test), mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline. These data reinforce the hypothesis that ASICs are involved in both mechanical and inflammatory pain, although the increased sensitivity of transgenic mice renders it unlikely that they are direct transducers of nociceptive stimuli.

Acid Sensing Ion Channels↗
PubMed2005

Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene.

Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRPalpha.

Animals↗
PubMed2005

The magnitude of mechanical allodynia in a rodent model of lumbar radiculopathy is dependent on strain and sex.

STUDY DESIGN: This study examined the differences in tactile hypersensitivity across 6 different strains of male mice, and between male and female rats of 3 different strains in a rodent model of low back pain associated with lumbar radiculopathy. OBJECTIVE: We investigated the possibility that differences in tactile allodynia following the same nerve root injury are affected by genotype and sex in rodents. SUMMARY OF BACKGROUND DATA: Low back pain associated with radiculopathy affects countless people throughout the world, encompassing a wide range of individual pain susceptibility. The roles of genetics and sex on differences in nociceptive sensitivities following lumbar nerve root injury have yet to be fully characterized. METHODS: Six strains of mice (BALB/cJ, CBA/J, C57BL/6J, 129P3/J, C3H/HeJ, and C58/J; all males) and male and female Sprague Dawley, Holtzman, and Long-Evans rats underwent a lumbar nerve root injury followed by assessment of tactile allodynia. RESULTS: The most sensitive mouse strains following nerve root injury were: 129P3/J, C58/J, and BALB/cJ; and the less sensitive strains were: C57BL/6J, C3H/HeJ, and CBA/J. Female Sprague Dawley and Long-Evans rats displayed increased hypersensitivity following nerve root injury compared to males. No sex differences were observed in Holtzman rats. CONCLUSIONS: Different mouse strains, and male and female rats that are exposed to identical nerve root injuries have diverse levels of tactile hypersensitivity, supporting the hypothesis that genetic factors and sex play a key role in radicular pain. Our results correlate with data compiled in identical mouse and rat strains after L5-L6 nerve ligation, suggesting that the precise nature of the injury is not relevant to the inheritance of neuropathic symptom sensitivity.

Animals↗
PubMed2005

Region-specific changes of calcium/calmodulin-dependent protein kinase IV in the mouse brain following chronic morphine treatment.

In this study, we examined changes in expression of calcium/calmodulin-dependent protein kinase IV (CaMKIV) in the mouse brain following chronic morphine treatment. Double immunohistochemical staining showed strong colocalization of CaMKIV with mu-opioid receptors. Chronic treatment with morphine produced an increase in expression of CaMKIV and phosphorylated cAMP response element-binding protein (pCREB) in the CA3 region of the hippocampus, whereas a decrease in CaMKIV and pCREB expression was observed in the caudate putamen. Interestingly, chronic morphine induced a decrease in protein expression of CaMKIV in the basolateral amygdale and the primary somatosensory cortex without any concomitant changes in pCREB. These findings suggest that CaMKIV-dependent signaling may play a role in chronic morphine-induced neuroplasticity in a brain region-specific manner.

Animals↗
PubMed2005

The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans.

Responses to painful stimuli are characterized by tremendous interindividual variability, and genetic factors likely account for some proportion of this variability. However, few studies have identified genetic contributions to experimental pain perception in humans. This experiment investigated whether the A118G single nucleotide polymorphism of the mu-opioid receptor gene ( OPRM1 ) was associated with responses to three different experimental pain modalities in a sample of 167 healthy volunteers (96 female, 71 male). Responses to thermal, mechanical, and ischemic pain were assessed in all subjects, and genotyping of OPRM1 was performed, which revealed that the rare A118G allele occurred in 24 females (25%) and 12 males (17%). Statistical analyses indicated that subjects with a rare allele had significantly higher pressure pain thresholds than those homozygous for the common allele. Also, a sex by genotype interaction emerged for heat pain ratings at 49 degrees C, such that the rare allele was associated with lower pain ratings among men but higher pain ratings among women. These data indicate an association of a common single nucleotide polymorphism of OPRM1 with mechanical pain responses and that this genotype may be associated with heat pain perception in a sex-dependent manner. This study examines the association of the A118G SNP of OPRM1 to experimental pain sensitivity. The results indicate that the rare allele is associated with higher pressure pain thresholds. These results support previous contentions that OPRM1 may be a pain-relevant gene; however, replication of these findings is needed.

Adult↗
PubMed2005

Influence of nociception and stress-induced antinociception on genetic variation in isoflurane anesthetic potency among mouse strains.

BACKGROUND: Genetic background influences anesthetic potency to suppress motor response to noxious stimulation (minimum alveolar concentration [MAC]) as well as nociceptive sensitivity in unmedicated animals. However, the influence on MAC of baseline sensitivity to the noxious stimuli used to assess MAC has virtually never been studied. The authors assessed room air nociceptive sensitivity and isoflurane MAC in multiple mouse strains. Isoflurane requirement for loss of righting response (MACLORR) was also measured. METHODS: One outbred and 10 inbred mouse strains were tested for latency to respond (in room air) to a tail clip (either 500 g or 2,000 g). Naive mice of the same 11 strains were tested for isoflurane MAC and MACLORR. To assess the role of opioid-mediated stress-induced antinociception, mice were also tested for nociceptive sensitivity after injection of naloxone (10 mg/kg) or saline. RESULTS: Robust strain differences were observed for all measures. The authors found that tail-clip latency (using a 500-g or 2,000-g clip, respectively) correlated significantly with MAC (r = -0.76 and -0.58, respectively) but not MACLORR (r = -0.10 and -0.26). Naloxone produced strain-dependent reductions in open air tail-clip latencies, and these reductions were also strongly correlated with MAC (r = -0.67 and -0.71). CONCLUSIONS: The authors suggest that genetic variability in isoflurane MAC (but not MACLORR) may reflect genetic variability in the underlying sensitivity to the noxious stimulus being used to measure MAC. This variable sensitivity to nociception in the awake state is at least partially mediated by endogenous antinociceptive mechanisms activated by the tail-clip stimulus itself.

Anesthetics, Inhalation↗
PubMed2004

Qualitative sex differences in kappa-opioid analgesia in mice are dependent on age.

The effects of aging on sex differences in analgesia from the kappa-opioid agonist, U50,488H (U50), were examined in C57BL/6J mice. U50 analgesia can be blocked by the N-methyl-d-aspartate receptor antagonist, MK-801 (MK), in male rodents and gonadectomized females, but not hormonally intact or estrogen-replaced females, suggesting the existence of alternate neurochemical mediation in females. We now report that MK antagonism of U50 analgesia is age-dependent in females. That is, reproductively senescent females display MK-sensitive U50 analgesia qualitatively similar to that displayed by males or hormonally deprived young females. Age-related reductions in U50 analgesic magnitude were also observed in females. Thus, age and gender are likely to alter the clinical efficacy of analgesic drugs active at kappa-opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred mouse strains.

Mechanical allodynia, or hypersensitivity to tactile stimuli, is a frequent clinical symptom of neuropathy. Large interindividual differences have been observed in neuropathic pain, both in susceptibility to its development and in its severity. Identification of genetic factors relevant to this variability would be of obvious utility. Although many animal models of neuropathic pain following peripheral nerve injury have been developed, most involve intricate surgeries and are thus poorly suited for large-scale linkage mapping investigations in the mouse. Recently, a schedule of intraperitoneal injections of the chemotherapeutic agent, paclitaxel (Taxol(R)), has been shown to produce a long-lasting, bilateral neuropathy in the rat, featuring hypersensitivity to mechanical, thermal and cold stimuli. We present here a survey of the responses of 10 inbred mouse strains to paclitaxel injections. Virtually all strains developed statistically significant mechanical allodynia, with one strain, DBA/2J, exhibiting especially robust changes. Strain sensitivities to paclitaxel-induced mechanical allodynia were similar to those obtained previously using a surgical model of neuropathic pain, supporting our contention that genetic sensitivity to mechanical allodynia is independent of the precise mode of induction. Using sensitive DBA/2 mice and a resistant strain, C57BL/6J, for comparison, we further characterized the paclitaxel model in mice by examining cold allodynia and thermal hyperalgesia. Both strains displayed equivalent cold allodynia but neither strain developed thermal hyperalgesia. The present data confirm a genetic component in mechanical allodynia using this model, while dissociating mechanical hypersensitivity from other pain modalities.

Analysis of Variance↗
PubMed2004

Mapping of a quantitative trait locus for morphine withdrawal severity.

Chronic morphine exposure results in physical dependence, manifested by physical symptoms during naloxone-precipitated withdrawal. Jumping frequency is widely considered the most sensitive and reliable index of withdrawal intensity in mice. Inbred mouse strains surveyed for naloxone-precipitated withdrawal display large and significant strain differences in jumping frequency, including an approximately tenfold difference between C57BL/6 and 129P3 mice. In the present study, (B6 x 129)F2 hybrid mice were given daily morphine injections for four days using an escalating dosing schedule, and naloxone-precipitated withdrawal on day 5 was measured. A full-genome scan for linkage to phenotypic data was performed using polymorphic microsatellite markers. Significant linkage was observed between withdrawal jumping frequencies and a 28 cM-wide region of Chromosome 1 (32-60 cM; peak at 51 cM), accounting for 20% of the overall phenotypic variance. Two other suggestive QTLs were found, on Chromosomes 5 and 10, and an additive model fitting all three loci accounted for 43% of the total variance. F2 mice were also assessed for changes in morphine analgesic potency using the tail-withdrawal test in dose-response studies on days 1 and 4. No linkage was observed between Chromosomes 1, 5, and 10 and morphine analgesic tolerance, suggestive of genetic dissociation of naloxone-precipitated withdrawal from morphine and chronic morphine intake per se. The significant quantitative trait locus for naloxone-precipitated withdrawal severity in morphine-dependent mice, which we name Depmq1, may prove to be of considerable heuristic value once the underlying gene or genes are identified.

Analgesics, Opioid↗
PubMed2004

Sex differences in pain and analgesia: the role of gonadal hormones.

There is now strong evidence for sex differences in pain and analgesia. These differences imply that gonadal steroid hormones such as estradiol and testosterone modulate sensitivity to pain and analgesia. The goal of this review is to present an overview of gonadal steroid modulation of pain and analgesia in animals and humans, and to describe mechanisms by which males' and females' biology may differentially predispose them to pain and to analgesic effects of drugs and stress. Evidence is presented to demonstrate that sex differences in pain and analgesia may be both quantitative and qualitative in nature. Current research suggests that sex-specific management of clinical pain will be a reality in the not-so-distant future.

Analgesics↗
PubMed2004

Modulation of morphine analgesia by site-specific N-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time.

Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors can modulate morphine analgesia in experimental animals and humans. However, this literature is highly inconsistent, with NMDA receptor antagonists variously shown to potentiate, attenuate or produce no effect on morphine analgesic magnitude. A number of factors influencing this modulation have been proposed, but no one has examined such factors simultaneously, and all existing studies in mice were conducted exclusively in male subjects. Thus, the influence of systemic administration of site-specific NMDA receptor antagonists-including dextromethorphan, dextrorphan, MK-801, LY235959, L-701,324, and Ro 25-6981-on morphine analgesia (15-45 mg/kg; 15, 30 and 60 min post-injection) was studied in male and female mice using the 49 degrees C tail-withdrawal test. We found that oral and intraperitoneal dextromethorphan, a low-affinity non-competitive antagonist, dose-dependently potentiated low-dose morphine analgesia but attenuated high-dose morphine analgesia. Dextrorphan and MK-801 were found to potentiate low- but not high-dose morphine analgesia. The competitive glutamate-site antagonist, LY235959, and glycine-site antagonist, L-701,324, potentiated morphine analgesia at all doses. In contrast, the polyamine (NR2B) site antagonist, Ro 25-6981, attenuated morphine analgesia at all doses. Strikingly, the non-competitive antagonists produced no modulation of morphine analgesia whatsoever in female mice, whereas no sex differences were observed using competitive or NR2B antagonists. These findings indicate that NMDA modulation of morphine analgesia is critically influenced by sex, site of antagonism, morphine dose and time after injection. Our data suggest that NMDA antagonism via competitive or glycine site antagonism might result in more reliable clinical effects on morphine analgesia in both sexes.

Animals↗