Voluntary exercise attenuates nociceptive abnormalities with no significant alterations of social interaction deficits in the BTBR mouse model of autism.

Due to the financial burden and undesired side effects of treatment options, researchers have begun exploring alternative methods of treating autism spectrum disorder (ASD). Based on research suggesting impressive health benefits of engaging in physical activity, exercise treatment to alleviate symptoms could be a more cost effective alternative to pharmaceutical interventions. This study examined the effects of physical exercise on nociceptive responses and social interactions in an autism mouse model (BTBR T+ Itpr3tf/J). Subjects (n = 32) were separated into groups (BTBR vs B6 controls) based on the genetic strain and activity condition they were assigned. When compared to B6 controls, the BTBR mice demonstrated thermal hypoalgesia that normalized following 5 weeks of voluntary wheel running. However, exercise did not significantly attenuate social interaction deficits in BTBR mice, despite scores trending toward a positive direction. These results suggest that exercise could serve as a potential additive to other therapies for abnormal nociception in individuals with Autism Spectrum Disorder.

Attention-deficit/hyperactivity disorder medication does not alter exercise-induced hypoalgesia following an acute bout of dynamic circuit resistance exercise.

The primary goal of this study was to investigate the effects of attention-deficit/hyperactivity disorder (ADHD) medications on exercise-induced hypoalgesia (EIH), heart rate, and perceived exertion. Thirty college-age students (10 Controls, 10 ADHD diagnosis, and 10 ADHD diagnosis with medications) completed 2 sessions: 1) a maximal testing session and 2) an experimental session consisting of 3 consecutive dynamic resistance exercise circuits comprised of 12 repetitions of 9 exercises at 60% of 1-repetition maximum using a 1:1 work to rest ratio. All participants, regardless of condition (Controls vs. ADHD without medications vs. ADHD with medications), displayed EIH accompanied by an increase in blood lactate, heart rate, and perceived exertion for the duration of the exercise bout. Therefore, the effects of resistance exercise are not altered by ADHD diagnosis or psychostimulant medication use for ADHD. These findings are intriguing given the known ergogenic and hypoalgesic effects of caffeine, a less potent stimulant.

Exercise-induced hypoalgesia: Pain tolerance, preference and tolerance for exercise intensity, and physiological correlates following dynamic circuit resistance exercise.

Previous research has demonstrated significant decreases in pain perception in healthy individuals following both aerobic and upper body resistance exercise, but research on circuit training has been limited. The purpose of the study was to determine the effects of a strenuous bout of dynamic circuit resistance exercise on pain threshold and pain tolerance in conjunction with changes in blood lactate levels, heart rate (HR), and perceived exertion. A sample of 24 college-age students participated in 2 sessions: (1) a maximal strength testing session and (2) a circuit training bout of exercise that consisted of 3 sets of 12 repetitions with a 1:1 work to rest ratio at 60% one-repetition maximum (1-RM) predicted from a three-repetition maximum (3-RM) for 9 exercises. Participants exhibited increases in pain tolerance, blood lactate levels, HR and perceived exertion following resistance exercise. Preference for exercise intensity was positively correlated with lactate post exercise and tolerance for exercise intensity was positively correlated with pain tolerance and lactate post exercise. In conclusion, this is the first study to demonstrate increases in pain tolerance following a dynamic circuit resistance exercise protocol and disposition for exercise intensity may influence lactate and pain responses to circuit resistance exercise.

Nicotine Deprivation Produces Deficits in Pain Perception that are Moderately Attenuated by Caffeine Consumption.

During withdrawal, nicotine users experience aversive withdrawal symptoms, such as increased nociceptive processing, which may be responsible for subsequent use. Smokers often consume more caffeine than non-smokers and the combined effects of these two psychoactive drugs result in an enhanced analgesic effect of nicotine. We examined the effects of caffeine (via coffee consumption) and nicotine withdrawal on pain perception in minimally deprived smokers and non-smokers. Pain threshold and pain tolerance were assessed using a radiant heat stimulus before and 30 minutes after caffeine consumption. Nicotine deprivation (2 hrs) produced increases in pain threshold and decreases in pain tolerance representative of hyperalgesia. When smokers are nicotine deprived, caffeine consumption diminished baseline elevations in pain threshold, but had no effect on pain tolerance. These data suggest that caffeine consumption can dampen deficits in sensory discrimination related to pain during nicotine deprivation by reducing pain threshold to levels representative of non-smoking controls.

Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala.

Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stress-induced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.

Predator odor stress alters corticotropin-releasing factor-1 receptor (CRF1R)-dependent behaviors in rats.

Humans with stress-related anxiety disorders exhibit increases in arousal and alcohol drinking, as well as altered pain processing. Our lab has developed a predator odor stress model that produces reliable and lasting increases in alcohol drinking. Here, we utilize this predator odor stress model to examine stress-induced increases in arousal, nociceptive processing, and alcohol self-administration by rats, and also to determine the effects of corticotropin-releasing factor-1 receptors (CRF1Rs) in mediating these behavioral changes. In a series of separate experiments, rats were exposed to predator odor stress, then tested over subsequent days for thermal nociception in the Hargreaves test, acoustic startle reactivity, or operant alcohol self-administration. In each experiment, rats were systemically injected with R121919, a CRF1R antagonist, and/or vehicle. Predator odor stress increased thermal nociception (i.e., hyperalgesia) and acoustic startle reactivity. Systemic administration of R121919 reduced thermal nociception and hyperarousal in stressed rats but not unstressed controls, and reduced operant alcohol responding over days. Stressed rats exhibited increased sensitivity to the behavioral effects of R121919 in all three tests, suggesting up-regulation of brain CRF1Rs number and/or function in stressed rats. These results suggest that post-stress alcohol drinking may be driven by a high-nociception high-arousal state, and that brain CRF1R signaling mediates these stress effects.

Nicotine dependence produces hyperalgesia: role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA).

Because tobacco use has a large negative health and financial impact on society, it is critical to identify the factors that drive excessive use. These factors include the aversive withdrawal symptoms that manifest upon cessation of tobacco use, and may include increases in nociceptive processing. Corticotropin-releasing factor (CRF) signalling in the central amygdala (CeA) has been attributed an important role in: (1) central processing of pain, (2) excessive nicotine use that results in nicotine dependence, and (3) in mediating the aversive symptoms that manifest following cessation of tobacco exposure. Here, we describe three experiments in which the main hypothesis was that CRF/CRF1 receptor (CRF1R) signalling in the CeA mediates nicotine withdrawal-induced increases in nociceptive sensitivity in rats that are dependent on nicotine. In Experiment 1, nicotine-dependent rats withdrawn from chronic intermittent (14-h/day) nicotine vapor exhibited decreased hind paw withdrawal latencies in response to a painful thermal stimulus in the Hargreaves test, and this effect was attenuated by systemic administration of the CRF1R antagonist, R121919. In Experiment 2, nicotine-dependent rats withdrawn from nicotine vapor exhibited robust increases in mRNA for CRF and CRF1Rs in CeA. In Experiment 3, intra-CeA administration of R121919 reduced thermal nociception only in nicotine-dependent rats. Collectively, these results suggest that nicotine dependence increases CRF/CRF1R signalling in the CeA that mediates withdrawal-induced increases in sensitivity to a painful stimulus. Future studies will build on these findings by exploring the hypothesis that nicotine withdrawal-induced reduction in pain thresholds drive excessive nicotine use via CRF/CRF1R signalling pathways.

Morphine-induced cognitive impairment is attenuated by induced pain in rats.

Opioid medications are frequently used in the effective treatment of intractable pain, but prolonged use of such medications can be complicated by a host of adverse effects. Among these adverse effects, tolerance and mental clouding can be especially disabling and can lead to both a reduced effectiveness of treatment and a reduced quality of life for many requiring treatment with these medications. Here we examined the relative contributions of complete Freund's adjuvant (CFA)-induced inflammatory pain and opioid medication on spatial memory for a well-learned task in male Sprague-Dawley rats. Although CFA, by itself, had little effect on spatial memory, morphine administered to pain-free animals produced profound detrimental effects on spatial memory that persisted longer than the analgesic effectiveness of the drug. However, no significant cognitive deficits were observed in animals receiving morphine in the presence of CFA-induced pain. Taken together, these results are evidence that the pain state of the organism can alter some of the negative effects of morphine.

Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease.

Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD(+)/Rhes(-/-) mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.

Measurement of CFA-induced hyperalgesia and morphine-induced analgesia in rats: dorsal vs plantar mechanical stimulation of the hindpaw.

OBJECTIVE: To compare the sensitivity of stimulating the plantar and dorsal hindpaw surfaces in the detection of mechanical allodynia and morphine analgesia. BACKGROUND: Several approaches are used to assess nociceptive reactivity to mechanical stimulation in animal models of pain. Although certain techniques seem to be favored for studying specific nociceptive conditions, the differences between techniques have not been directly compared and characterized. We chose to compare methods employing stimulation applied to the dorsum of the paw with stimulation of the plantar surface to demonstrate the utility of each approach in determining baseline nociceptive thresholds, changes in those thresholds after injury, and analgesic efficacy. METHODS: Withdrawal thresholds from mechanical stimulation applied to the dorsal and plantar surface of the hindpaw were measured in rats treated with morphine after receiving subcutaneous injections of complete Freund's adjuvant (CFA) using Semmes-Weinstein (S-W) monofilaments and electro von Frey (EVF) stimulation. RESULTS: In contrast to stimulation of the dorsal surface, plantar hindpaw stimulation seldom elicited an aversive withdrawal response. Differences in withdrawal response from baseline were only detectable within the first 5 hours post-CFA and only with EVF stimulation. No significant differences in stimulation techniques were observed after the initial 5-hour window. Effective dose 50 (ED(50)) for analgesic efficacy was consistently lower using dorsal stimulation. CONCLUSIONS: Stimulation of the plantar surface of the paw is superior for detecting small changes in paw sensitivity at very low stimulus intensities, whereas stimulation of the dorsal surface is superior for delineating baseline pain thresholds and for detecting robust analgesia. CLINICAL RELEVANCE: Reliable and sensitive assessment of animal pain behaviors is critical to translational pain research. This study demonstrates the importance of using proper test protocols in animal studies and its implication in preclinical screening of potential analgesics.

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence.

Rhes, the Ras Homolog Enriched in Striatum, is an intermediate-size GTP binding protein. Although its full functions are not yet known, it has been shown to affect signaling and behaviors mediated by G protein-coupled receptors. Here we have tested whether Rhes affects behaviors mediated by opioid receptors. Wild type and rhes-deficient mice were administered morphine and tested for analgesia in formalin and tail flick tests. Rhes⁻/⁻ mice showed significantly enhanced analgesia in both tests relative to rhes+/+ mice. Furthermore, rhes⁻/⁻ mice did not display tolerance to repeated morphine administration and displayed significantly less withdrawal than rhes+/+ mice. These findings indicate that Rhes is involved in behaviors mediated by mu opioid receptors and in the adaptive response to repeated morphine administration.

The effect of wanted posters on prospective and retrospective memory.

The experiment tested prospective and retrospective memory for a person pictured on a wanted poster. Participants monitored the videotaped activity of a computer lab; one of their duties involved reporting if they saw a computer hacker. Half viewed a wanted poster of the hacker before the monitoring task and half after. For half the participants, the hacker appeared during monitoring and for half not. A diagnosticity ratio comparing the correct prospective memory identifications with false positive identifications showed that a prospective identification was 3.35 times more likely to be accurate than inaccurate. For those viewing the wanted poster after monitoring, the diagnosticity ratio was 1.21. Based on diagnosticity, a prospective identification had more value than a retrospective identification.