- Email: [email protected]
(271) Behavioral and physiological effects of poor diet in mice
Abstracts
D14 Receptors - G-Protein Coupled (268) Female-specific effects of a serotonin 2A receptor (HTR2A) genetic variant on TMD pain and psychological phenotypes S Smith, E Bair, G Slade, C Ostrum, E Helgeson, R Fillingim, J Greenspan, R Ohrbach, R Dubner, W Maixner, and L Diatchenko; University of North Carolina, Chapel Hill, NC Temporomandibular disorders (TMD) represent a major source of chronic orofacial pain, but their etiology is not well understood. In order to identify genetic risk factors for chronic TMD, we have examined genetic polymorphisms in two large candidate gene association studies that used case-control designs. The discovery cohort, the UNC-TMD study, included 200 chronic TMD cases and 198 pain-free controls, all of which were white females. For replication we used the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study; association analyses included 166 chronic TMD cases and 1442 healthy controls, of both sexes and varied racial backgrounds. Genotyping in both studies was performed using the Algynomics Pain Research Panel, which assesses 350 candidate pain genes. Association testing was performed using logistic regression in PLINK. The strongest association observed in the UNC-TMD study was with SNP rs9316233 in the HTR2A serotonin receptor 2A gene (p=2.3x10-4, minor allele G protective). The association was confirmed in the OPPERA cohort (p=0.03, G protective). When combined, the two cohorts showed a strong effect of the SNP (meta-analysis p=5.0x10-5, OR=0.55). Furthermore, in OPPERA the association was stronger in non-Hispanic whites (p=0.005) and females (p=0.004), suggesting gene x strata interactions. In OPPERA, we further examined a range of psychological, clinical, and sensory endophenotypes as dependent variables using linear regression to model the genetic association, and again observed sex-specific associations. In females, additional copies of the G allele consistently corresponded with decreased psychological distress and pain, while in males there was lesser or no genetic effect. Phenotypes exhibiting notable gene x sex interactions included measures of somatization, depression, catastrophizing, and perceived stress, as well as pain sensitivity. These findings may partially explain sex differences observed in clinical pain susceptibility and associated characteristics, and may point to strategies for personalized treatments for pain.
(269) Variations in opioid receptor genes are associated with breast pain in women prior to and with mild and severe persistent breast pain after breast cancer surgery B Aouizerat, K Kober, J Levine, S Paul, B Cooper, B Schmidt, and C Miaskowski; University of California at San Francisco, San Francisco, CA Previous work from our team found that breast pain occurred in 28.2% of women (n=398) who were about to undergo breast cancer surgery. In addition, using growth mixture modeling we identified four latent classes of patients with distinct trajectories of worst breast pain, reported prior to and monthly for 6 months after surgery. Four subgroups were identified: a ‘‘No Pain’’ (n=126, 31.7%), a ‘‘Mild Pain’’ (numeric rating scale (NRS) of 3 that remained constant; n=173, 43.4%), a ‘‘Moderate Pain’’ (NRS of 2 that increased over time; n=53, 13.3%), and a ‘‘Severe Pain’’ (NRS of 8 that remained constant; n=53, 13.3%) group. We hypothesized that variations in the opioid-receptorlike, delta, kappa, mu, and sigma receptor genes would be associated with preoperative breast pain and with Mild and Severe Pain groups. The purpose of this study was to test for associations between single nucleotide polymorphisms (SNPs) in 5 opioid receptor genes and the occurrence of preoperative breast pain and with membership in the Mild and Severe Pain groups. Multivariable logistic regression analyses were used to identify those SNPs that were associated with the occurrence of preoperative breast pain and for Mild Pain or Severe Pain group membership compared to the No Pain group while controlling for relevant demographic, clinical, and genomic characteristics. Variations in kappa (rs6985606, p=0.034), mu (rs11155954, p=0.016), and sigma (rs10814130, p=0.024) opioid receptor genes were associated with the occurrence of preoperative breast pain. The same SNP in the mu opioid receptor gene (rs13193545) was associated with Mild (p=0.045) and Severe (p=0.042) Pain group membership as compared to the No Pain group. Opioid receptor gene variations and specific demographic and clinical characteristics are associated with preoperative breast pain and with persistent mild and severe breast pain after breast cancer surgery and warrant replication in an independent sample.
The Journal of Pain
S43
D15 Receptors - Other Transporters (270) Biochemical, mitochondrial alterations of PPAR-g agonist in rat model of neuropathic pain R Pottabathini and A Kumar; Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, Chandigarh, India Oxidative stress and mitochondrial dysfunction has been suggested to play key role in the development and maintenance of the neuropathic pain. The present study was designed to explore the role of oxidative stress in the spinal nerve ligation (SNL) induced neuropathic pain with the help of various behavioral, biochemical, mitochondrial and cellular alterations in rats. In the present study, unilateral lumbar L5 and L6 spinal nerves were ligated to induce neuropathic pain in rats. Behavioral parameters were assessed on the day before ligation and successively on day 7th, 14th, 21st and 28th post ligation. Oxidative stress parameters and mitochondrial enzyme functions were assessed on day 28 after behavioral observations. SNL resulted in significant increase in mechanical allodynia, mechanical hyperalgesia, cold allodynia and heat hyperalgesia as assessed by Vonfrey, Randall Selitto, Acetone drop and Hot plate tests respectively. SNL also resulted in significant increase in oxidative stress parameters (increased lipid peroxidation, nitrite, reduced superoxide dismutase, catalase and glutathione) in lumbar spinal cord. Mitochondrial enzyme complexes activities were significantly inhibited by SNL. Pioglitazone (a PPAR gamma agonist) treatment (10 and 20 mg/kg, i.p.) for 28 days significantly reversed the various behavioral, biochemical and mitochondrial alterations in SNL treated animals. Results of the present study show that ameliorative potential of pioglitazone in SNL induced behavioral and mitochondrial alterations which may be further attributed to inhibition of oxidative stress and mitochondrial dysfunction in rats.
E. Systems (Physiology, Anatomy, Animal Models) E01 Animal Models of Acute, Inflammatory, and Postoperative Pain (271) Behavioral and physiological effects of poor diet in mice R Sorge, S Totsch, M Waite, A Tomkovich, and T Quinn; University of Alabama at Birmingham, Birmingham, AL Obesity rates in the United States are climbing rapidly, and obesity is often comorbid with chronic pain. In many instances, obesity is a result of poor diet choices. Therefore, we utilized a cafeteria diet (CAF) and a total western diet (TWD) in separate experiments to investigate the functional and physiological consequences of poor diet in mice. The CAF was used to model human-like nutrient intake from junk foods. During ten weeks on the CAF, the mice had elevated mechanical and thermal thresholds when compared to regular dietfed controls. In addition, there was a significant increase in blood C-reactive protein levels. Thus, ten weeks of the CAF had significant behavioral and physiological impact. To have tighter control over nutrient intake, we utilized a commercially-available total western diet (TWD), based on the NHANES, for thirteen weeks. Similar to the CAF, the thresholds of the TWD-fed mice were significantly elevated in both thermal and mechanical tests. Quantitative magnetic resonance (QMR) revealed a significant increase in fat mass with a concomitant decrease in lean mass, in the TWD mice. Additionally, there were significant increases in serum leptin levels as well as inflammatory cytokines (IL-6, IL-1b and TNF-a). Following chronic pain induction using Complete Freund’s adjuvant (CFA), allodynia was more pronounced and recovery was significantly prolonged in the TWD mice. Therefore, although sensitivity to acute stimuli is reduced, long term effects of poor diet resulted in longer recovery time from injury, likely as a consequence of chronic systemic inflammation. Future work will examine the role of diet on neuropathic injury.
D14 Receptors - G-Protein Coupled (268) Female-specific effects of a serotonin 2A receptor (HTR2A) genetic variant on TMD pain and psychological phenotypes S Smith, E Bair, G Slade, C Ostrum, E Helgeson, R Fillingim, J Greenspan, R Ohrbach, R Dubner, W Maixner, and L Diatchenko; University of North Carolina, Chapel Hill, NC Temporomandibular disorders (TMD) represent a major source of chronic orofacial pain, but their etiology is not well understood. In order to identify genetic risk factors for chronic TMD, we have examined genetic polymorphisms in two large candidate gene association studies that used case-control designs. The discovery cohort, the UNC-TMD study, included 200 chronic TMD cases and 198 pain-free controls, all of which were white females. For replication we used the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study; association analyses included 166 chronic TMD cases and 1442 healthy controls, of both sexes and varied racial backgrounds. Genotyping in both studies was performed using the Algynomics Pain Research Panel, which assesses 350 candidate pain genes. Association testing was performed using logistic regression in PLINK. The strongest association observed in the UNC-TMD study was with SNP rs9316233 in the HTR2A serotonin receptor 2A gene (p=2.3x10-4, minor allele G protective). The association was confirmed in the OPPERA cohort (p=0.03, G protective). When combined, the two cohorts showed a strong effect of the SNP (meta-analysis p=5.0x10-5, OR=0.55). Furthermore, in OPPERA the association was stronger in non-Hispanic whites (p=0.005) and females (p=0.004), suggesting gene x strata interactions. In OPPERA, we further examined a range of psychological, clinical, and sensory endophenotypes as dependent variables using linear regression to model the genetic association, and again observed sex-specific associations. In females, additional copies of the G allele consistently corresponded with decreased psychological distress and pain, while in males there was lesser or no genetic effect. Phenotypes exhibiting notable gene x sex interactions included measures of somatization, depression, catastrophizing, and perceived stress, as well as pain sensitivity. These findings may partially explain sex differences observed in clinical pain susceptibility and associated characteristics, and may point to strategies for personalized treatments for pain.
(269) Variations in opioid receptor genes are associated with breast pain in women prior to and with mild and severe persistent breast pain after breast cancer surgery B Aouizerat, K Kober, J Levine, S Paul, B Cooper, B Schmidt, and C Miaskowski; University of California at San Francisco, San Francisco, CA Previous work from our team found that breast pain occurred in 28.2% of women (n=398) who were about to undergo breast cancer surgery. In addition, using growth mixture modeling we identified four latent classes of patients with distinct trajectories of worst breast pain, reported prior to and monthly for 6 months after surgery. Four subgroups were identified: a ‘‘No Pain’’ (n=126, 31.7%), a ‘‘Mild Pain’’ (numeric rating scale (NRS) of 3 that remained constant; n=173, 43.4%), a ‘‘Moderate Pain’’ (NRS of 2 that increased over time; n=53, 13.3%), and a ‘‘Severe Pain’’ (NRS of 8 that remained constant; n=53, 13.3%) group. We hypothesized that variations in the opioid-receptorlike, delta, kappa, mu, and sigma receptor genes would be associated with preoperative breast pain and with Mild and Severe Pain groups. The purpose of this study was to test for associations between single nucleotide polymorphisms (SNPs) in 5 opioid receptor genes and the occurrence of preoperative breast pain and with membership in the Mild and Severe Pain groups. Multivariable logistic regression analyses were used to identify those SNPs that were associated with the occurrence of preoperative breast pain and for Mild Pain or Severe Pain group membership compared to the No Pain group while controlling for relevant demographic, clinical, and genomic characteristics. Variations in kappa (rs6985606, p=0.034), mu (rs11155954, p=0.016), and sigma (rs10814130, p=0.024) opioid receptor genes were associated with the occurrence of preoperative breast pain. The same SNP in the mu opioid receptor gene (rs13193545) was associated with Mild (p=0.045) and Severe (p=0.042) Pain group membership as compared to the No Pain group. Opioid receptor gene variations and specific demographic and clinical characteristics are associated with preoperative breast pain and with persistent mild and severe breast pain after breast cancer surgery and warrant replication in an independent sample.
The Journal of Pain
S43
D15 Receptors - Other Transporters (270) Biochemical, mitochondrial alterations of PPAR-g agonist in rat model of neuropathic pain R Pottabathini and A Kumar; Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, Chandigarh, India Oxidative stress and mitochondrial dysfunction has been suggested to play key role in the development and maintenance of the neuropathic pain. The present study was designed to explore the role of oxidative stress in the spinal nerve ligation (SNL) induced neuropathic pain with the help of various behavioral, biochemical, mitochondrial and cellular alterations in rats. In the present study, unilateral lumbar L5 and L6 spinal nerves were ligated to induce neuropathic pain in rats. Behavioral parameters were assessed on the day before ligation and successively on day 7th, 14th, 21st and 28th post ligation. Oxidative stress parameters and mitochondrial enzyme functions were assessed on day 28 after behavioral observations. SNL resulted in significant increase in mechanical allodynia, mechanical hyperalgesia, cold allodynia and heat hyperalgesia as assessed by Vonfrey, Randall Selitto, Acetone drop and Hot plate tests respectively. SNL also resulted in significant increase in oxidative stress parameters (increased lipid peroxidation, nitrite, reduced superoxide dismutase, catalase and glutathione) in lumbar spinal cord. Mitochondrial enzyme complexes activities were significantly inhibited by SNL. Pioglitazone (a PPAR gamma agonist) treatment (10 and 20 mg/kg, i.p.) for 28 days significantly reversed the various behavioral, biochemical and mitochondrial alterations in SNL treated animals. Results of the present study show that ameliorative potential of pioglitazone in SNL induced behavioral and mitochondrial alterations which may be further attributed to inhibition of oxidative stress and mitochondrial dysfunction in rats.
E. Systems (Physiology, Anatomy, Animal Models) E01 Animal Models of Acute, Inflammatory, and Postoperative Pain (271) Behavioral and physiological effects of poor diet in mice R Sorge, S Totsch, M Waite, A Tomkovich, and T Quinn; University of Alabama at Birmingham, Birmingham, AL Obesity rates in the United States are climbing rapidly, and obesity is often comorbid with chronic pain. In many instances, obesity is a result of poor diet choices. Therefore, we utilized a cafeteria diet (CAF) and a total western diet (TWD) in separate experiments to investigate the functional and physiological consequences of poor diet in mice. The CAF was used to model human-like nutrient intake from junk foods. During ten weeks on the CAF, the mice had elevated mechanical and thermal thresholds when compared to regular dietfed controls. In addition, there was a significant increase in blood C-reactive protein levels. Thus, ten weeks of the CAF had significant behavioral and physiological impact. To have tighter control over nutrient intake, we utilized a commercially-available total western diet (TWD), based on the NHANES, for thirteen weeks. Similar to the CAF, the thresholds of the TWD-fed mice were significantly elevated in both thermal and mechanical tests. Quantitative magnetic resonance (QMR) revealed a significant increase in fat mass with a concomitant decrease in lean mass, in the TWD mice. Additionally, there were significant increases in serum leptin levels as well as inflammatory cytokines (IL-6, IL-1b and TNF-a). Following chronic pain induction using Complete Freund’s adjuvant (CFA), allodynia was more pronounced and recovery was significantly prolonged in the TWD mice. Therefore, although sensitivity to acute stimuli is reduced, long term effects of poor diet resulted in longer recovery time from injury, likely as a consequence of chronic systemic inflammation. Future work will examine the role of diet on neuropathic injury.