scholarly journals TNF-Alpha as an Initiator of Allodynia and Anxiety-Like Behaviors in a Preclinical Model of PTSD and Comorbid Pain

2021 ◽  
Vol 12 ◽  
Author(s):  
Patrick Dib ◽  
Yong Zhang ◽  
Michael A. Ihnat ◽  
Randle M. Gallucci ◽  
Kelly M. Standifer
Keyword(s):  
Traumatic Event ◽  
Elevated Serum ◽  
Thermal Hyperalgesia ◽  
Female Rats ◽  
Preclinical Model ◽  
Orphanin Fq ◽  
Post Traumatic Stress ◽  
Male And Female Rats ◽  
Tnf Α ◽  
Nociceptive Responses

Post-Traumatic Stress Disorder (PTSD) is a debilitating mental health disorder that occurs after exposure to a traumatic event. Patients with comorbid chronic pain experience affective distress, worse quality of life, and poorer responses to treatments for pain or PTSD than those with either condition alone. FDA-approved PTSD treatments are often ineffective analgesics, requiring additional drugs to treat co-morbid symptoms. Therefore, development of new treatment strategies necessitate a better understanding of the pathophysiology of PTSD and comorbid pain. The single prolonged stress (SPS) model of PTSD induces the development of persistent mechanical allodynia and thermal hyperalgesia. Increased Nociceptin/Orphanin FQ (N/OFQ) levels in serum and CSF accompany these exaggerated nociceptive responses, as well as increased serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF-α). Therefore, the primary goal was to determine the role of TNF-α in the development of SPS-induced allodynia/hyperalgesia and elevated serum and CNS N/OFQ using two approaches: TNF-α synthesis inhibition, and blockade with anti-TNF-α antibody that acts primarily in the periphery. Administration of TNF-α synthesis blocker, thalidomide (THL), immediately after SPS prevented increased TNF-α and development of allodynia and hyperalgesia. The THL effect lasted at least 21 days, well after thalidomide treatment ended (day 5). THL also prevented SPS-induced increases in serum N/OFQ and reversed regional N/OFQ mRNA expression changes in the CNS. Serum TNF-α increases detected at 4 and 24 h post SPS were not accompanied by blood brain barrier disruption. A single injection of anti-TNF-α antibody to male and female rats during the SPS procedure prevented the development of allodynia, hyperalgesia, and elevated serum N/OFQ, and reduced SPS-induced anxiety-like behaviors in males. Anti-TNFα treatment also blocked development of SPS-induced allodynia in females, and blocked increased hypothalamic N/OFQ in males and females. This suggests that a peripheral TNF-α surge is necessary for the initiation of allodynia associated with SPS, as well as the altered central and peripheral N/OFQ that maintains nociceptive sensitivity. Therefore, early alleviation of TNF-α provides new therapeutic options for investigation as future PTSD and co-morbid pain treatments.

scholarly journals Behavior and Fos activation reveal that male and female rats differentially assess affective valence during CTA learning and expression

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260577
Author(s):  
Alyssa Bernanke ◽  
Elizabeth Burnette ◽  
Justine Murphy ◽  
Nathaniel Hernandez ◽  
Sara Zimmerman ◽  
...  
Keyword(s):  
Sex Differences ◽  
D2 Receptor ◽  
Brain Regions ◽  
D1 Receptor ◽  
Neural Mechanisms ◽  
Female Rats ◽  
Post Traumatic Stress ◽  
Affective Valence ◽  
Male And Female Rats ◽  
Males And Females

Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.

scholarly journals Orphanin FQ/Nociceptin Is a Physiological Regulator of Prolactin Secretion in Female Rats

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5087-5093 ◽  
Author(s):  
Matthew Chesterfield ◽  
James Janik ◽  
Emily Murphree ◽  
Courtney Lynn ◽  
Erin Schmidt ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Prolactin Secretion ◽  
Secretory Response ◽  
Female Rats ◽  
Receptor Subtype ◽  
Orphanin Fq ◽  
Prolactin Release ◽  
Endogenous Opioid Peptide ◽  
Male And Female Rats ◽  
Prolactin Response

Orphanin FQ/nociceptin (OFQ/N), the most recently identified endogenous opioid peptide, stimulates prolactin secretion in both male and female rats. OFQ/N, however, did not elicit this stimulatory effect through the μ-, δ-, or κ-opiate receptor subtype. The role OFQ/N plays in prolactin regulation under physiological conditions and its mechanism of action are not known. The purpose of these studies was to determine the physiological significance and pharmacological specificity of the prolactin secretory response to OFQ/N. In addition, the role of the tuberoinfundibular dopaminergic (TIDA) neurons in mediating this response was examined. Opioid receptor-like-1 (ORL-1) receptors were blocked by pretreatment with compound B (Comp B), a purported OFQ/N antagonist, or receptor synthesis was disrupted by pretreatment with ORL-1 receptor antisense oligonucleotides. The prolactin secretory response to OFQ/N administration in diestrous females was measured. Furthermore, the suckling-induced prolactin response was also determined after Comp B pretreatment. TIDA neuronal activity was quantified in diestrous female rats to determine whether OFQ/N stimulates prolactin release by inhibiting TIDA neurons. OFQ/N significantly inhibited the TIDA neurons by 1 min, preceding the prolactin secretory response. Both Comp B and antisense pretreatment blocked the stimulatory effects of OFQ/N on prolactin release, and Comp B abolished the suckling-induced prolactin response. These studies indicate that OFQ/N is a potent stimulus for prolactin secretion in female rats and that it mediates this effect by rapid and transient inhibition of TIDA neuronal activity. Furthermore, OFQ/N plays a physiologically significant role in the regulation of prolactin secretion during lactation, and it mediates its effects via actions at the ORL-1 receptor subtype.

Orphanin FQ stimulates prolactin and growth hormone release in male and female rats

1998 ◽  
Vol 807 (1-2) ◽  
pp. 228-233 ◽  
Author(s):  
Winnifred Bryant ◽  
James Janik ◽  
Michael Baumann ◽  
Phyllis Callahan
Keyword(s):  
Growth Hormone ◽  
Female Rats ◽  
Hormone Release ◽  
Growth Hormone Release ◽  
Orphanin Fq ◽  
Male And Female ◽  
Male And Female Rats

scholarly journals Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

2013 ◽  
Vol 305 (9) ◽  
pp. E1154-E1164 ◽  
Author(s):  
Mayur J. Patil ◽  
Shivani B. Ruparel ◽  
Michael A. Henry ◽  
Armen N. Akopian
Keyword(s):  
Sensory Neurons ◽  
Inflammatory Pain ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Inflammatory Responses ◽  
Thermal Hyperalgesia ◽  
Female Rats ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Male And Female Rats

Prolactin (PRL) is a hormone produced in the anterior pituitary but also synthesized extrapituitary where it can influence diverse cellular processes, including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sex-dependent inflammatory pain is unknown. We found that PRL regulates transient receptor potential (TRP) channels in a sex-dependent manner in sensory neurons. At >20 ng/ml, PRL sensitizes TRPV1 in female, but not male, neurons. This effect is mediated by PRL receptor (PRL-R). Likewise, TRPA1 and TRPM8 were sensitized by 100 ng/ml PRL only in female neurons. We showed that complete Freund adjuvant (CFA) upregulated PRL levels in the inflamed paw of both male and female rats, but levels were higher in females. In contrast, CFA did not change mRNA levels of long and short PRL-R in the dorsal root ganglion or spinal cord. Analysis of PRL and PRL-R knockout (KO) mice demonstrated that basal responses to cold stimuli were only altered in females, and with no significant effects on heat and mechanical responses in both sexes. CFA-induced heat and cold hyperalgesia were not changed in PRL and PRL-R KO compared with wild-type (WT) males, whereas significant reduction of heat and cold post-CFA hyperalgesia was detected in PRL and PRL-R KO females. Attenuation of CFA-induced mechanical allodynia was observed in both PRL and PRL-R KO females and males. Thermal hyperalgesia in PRL KO females was restored by administration of PRL into hindpaws. Overall, we demonstrate a sex-dependent regulation of peripheral inflammatory hyperalgesia by the PRL system.

EFFECT OF MESENCEPHALIC STIMULATION ON THE RELEASE OF GONADOTROPHINS

1970 ◽  
Vol 48 (4) ◽  
pp. 527-539 ◽  
Author(s):  
H. F. CARRER ◽  
S. TALEISNIK
Keyword(s):  
Follicle Stimulating Hormone ◽  
Elevated Serum ◽  
Serum Levels ◽  
Female Rats ◽  
Continuous Illumination ◽  
Electrolytic Deposition ◽  
Inhibitory Effects ◽  
Male And Female Rats ◽  
Serum Lh ◽  
Stimulation Of

SUMMARY Different regions of the midbrain were stimulated by electrolytic deposition of iron from stainless steel unipolar electrodes. Electrochemical stimulation of the ventral tegmental area (VTA), the raphe nuclei or the peri-aqueductal grey in rats in pro-oestrus was effective in preventing spontaneous ovulation. No blockade of ovulation was observed by stimulating other mesencephalic structures. After stimulation in the VTA there was a significant decrease of the elevated serum levels of luteinizing hormone (LH) found after an injection of progesterone into pro-oestrous rats or into ovariectomized—oestrogen-primed animals. In contrast, electrochemical stimulation of the dorsal mesencephalic tegmentum, lateral and inferior to the peri-aqueductal grey, in rats in which spontaneous ovulation had been blocked by continuous illumination, resulted in an ovulatory response. Serum LH was found to increase in gonadectomized—oestrogen-treated male and female rats after stimulating this area. No significant changes in serum follicle-stimulating hormone were found after stimulation in the ventral or dorsal tegmentum. It is concluded that both stimulatory and inhibitory influences on the release of gonadotrophin can be evoked by stimulating mesencephalic structures. The stimulatory and inhibitory effects could depend on the activation of noradrenergic and serotoninergic systems, respectively.

Abstract T P240: Intravenous Injections of Microrna 363 Mimic Promotes Neuroprotection in Middle Aged Females in an Ischemic Stroke Model

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Amutha Selvamani ◽  
Farida Sohrabji
Keyword(s):  
Infarct Volume ◽  
Expression Patterns ◽  
Elevated Serum ◽  
Treated Group ◽  
Female Rats ◽  
Pcr Analysis ◽  
Circulating Microrna ◽  
Middle Aged ◽  
Post Stroke ◽  
Male And Female Rats

Background: Analysis of circulating microRNA in young and middle aged male and female rats revealed distinct expression patterns of post-stroke microRNAs (Selvamani et al., 2014). Mir-363 expression was inversely related to infarct volume, such that adult females, who display the smallest infarct volumes, had the highest expression of miR363. Based on this association, we hypothesized that mir-363 may promote survival of ischemic neurons. As proof of concept, the present study utilized middle aged females to investigate the role of miR-363 in neuroprotection. Methods: Middle aged (12 mo) female rats were subject to middle cerebral artery occlusion (MCAo). At 4h post-stroke, animals received a tail-vein injection of miR-363 or scrambled control. Vibrissae-elicited forelimb placement (VIB) test was performed pre and post MCAo to assess motor deficits. Blood samples were drawn at 2d and 5d post stroke. All animals were terminated at 5d post MCAo and the brains processed for infarct analysis by standard histological procedures. Total RNA isolated from serum and brain was subject to QPCR amplification for miR-363 and U6 (normalization control) Results: IV injections of mir363 significantly elevated serum expression of this microRNA as compared to animals injected with scrambles control oligos, when measured 2d post stroke. Infarct volumes (cortex and striatum), at 5d post stroke, were significantly reduced in the miR-363 treated group as compared to controls (p ≤ 0.001). VIB-test indicated significant motor recovery post-stroke in the contralateral limb in miR-363 mimic treated group as compared to controls. RT-PCR analysis of brain tissue showed higher expression of miR-363 in the left (ischemic) hemisphere in the miR-363 mimic group while, no difference was observed in the non-ischemic, indicating that the mimetic is recruited to the ischemic site. Conclusion: The present study underscores the value of miRNA profiling in populations with different stroke outcomes as a strategy to identify new therapeutic targets for stroke.

scholarly journals Effect of alloxan-induced diabetes on serum and cardiac butyrylcholinesterases in the rat

2002 ◽  
Vol 175 (1) ◽  
pp. 241-250 ◽  
Author(s):  
KR Dave ◽  
SS Katyare
Keyword(s):  
Insulin Treatment ◽  
Elevated Serum ◽  
Diabetic Rats ◽  
Female Rats ◽  
Diabetic Rat ◽  
Slight Reduction ◽  
Bche Activity ◽  
Male And Female Rats ◽  
Membrane Bound ◽  
Substrate Kinetics

Elevated serum butyrylcholinesterase (BChE) activity in the diabetic rat, mouse and human is very evident. The source of the increased level of BChE in the diabetic condition is not known. The effect of diabetes on cardiac BChE has not been studied so far, in spite of high BChE levels in the heart. In the present study, we investigated the effect of alloxan-induced diabetes on serum and on the soluble as well as the membrane-bound form of cardiac BChE activity and their substrate kinetics. We included rats of both sexes in the study. Serum BChE activity increased only in male diabetic rats (2.3-fold), while the activities of the soluble as well as the membrane-bound form of cardiac BChE activity increased 2.2- to 2.8-fold in male diabetic rats. A smaller increase (30%) was observed in the activity of the membrane-bound form of cardiac BChE in female diabetic rats. A slight reduction in BChE activity was observed in male and female rats after insulin treatment. The activity ratio of the soluble to the membrane-bound form of cardiac BChE was higher in diabetic and insulin-treated diabetic rats as compared with controls. The K(m) values of component II of the serum and soluble forms of cardiac BChE were comparable. In conclusion, the diabetes-induced increase in serum and cardiac BChE activity was sex dependent. Insulin was not able to rectify the diabetes-induced abnormalities in serum and cardiac BChE activity. The heart could be one of the possible sources of the increased level of serum BChE.

scholarly journals Behavioral Expression of Contextual Fear in Male and Female Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Amanda S. Russo ◽  
Ryan G. Parsons
Keyword(s):  
Fear Conditioning ◽  
Freezing Behavior ◽  
Contextual Fear Conditioning ◽  
Female Rats ◽  
Post Traumatic Stress ◽  
Male And Female ◽  
Contextual Fear ◽  
Male And Female Rats ◽  
Fear Potentiated Startle ◽  
Fear And Anxiety

The study of fear conditioning has led to a better understanding of fear and anxiety-based disorders such as post-traumatic stress disorder (PTSD). Despite the fact many of these disorders are more common in women than in men, the vast majority of work investigating fear conditioning in rodents has been conducted in males. The goal of the work presented here was to better understand how biological sex affects contextual fear conditioning and expression. To this end, rats of both sexes were trained to fear a specific context and fear responses were measured upon re-exposure to the conditioning context. In the first experiment, male and female rats were given context fear conditioning and tested the next day during which freezing behavior was measured. In the second experiment, rats were trained and tested in a similar fashion while fear-potentiated startle and defecation were measured. We found that males showed more freezing behavior than females during a fear expression test. The expression of fear-potentiated startle did not differ between sexes, while males exhibited more defecation during a test in a novel context. These data suggest that the expression of defensive behavior differs between sexes and highlight the importance of using multiple measures of fear when comparing between sexes.

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