Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms

Deep Inelastic Scattering and Gauge/String Duality

We study deep inelastic scattering in gauge theories which have dual string descriptions. As a function of $gN$ we find a transition. For small $gN$, the dominant operators in the OPE are the usual ones, of approximate twist two, corresponding to scattering from weakly interacting partons. For large $gN$, double-trace operators dominate, corresponding to scattering from entire hadrons (either the original `valence' hadron or part of a hadron cloud.) At large $gN$ we calculate the structure functions. As a function of Bjorken $x$ there are three regimes: $x$ of order one, where the scattering produces only supergravity states; $x$ small, where excited strings are produced; and, $x$ exponentially small, where the excited strings are comparable in size to the AdS space. The last regime requires in principle a full string calculation in curved spacetime, but the effect of string growth can be simply obtained from the world-sheet renormalization group.Comment: 52 pages, 10 figure

Sex differences in hypothalamic responses to stress following chronic intermittent ethanol exposure

Alcohol use disorder (AUD) is a chronic, relapsing disorder that represents a substantial societal burden at a global scale. In the US alone, AUD is associated with societal and financial costs exceeding $249 billion per year. While many use alcohol for its reported anxiolytic and gregarious properties, consuming alcohol directly activates the hypothalamic stress axis. Persons with AUD, that are consistently exposed to this stressful stimulus, are known to have alterations in the acute response to alcohol. Little is known about how chronic ethanol exposure alters the plastic and metaplastic responses of stress, per se.Relapse remains a main barrier in the pharmaceutical treatment of AUDs. While there are some medications currently available for AUD, none explicitly target the hypothalamic-pituitary-adrenal (HPA) axis. Further, sex is an essential variable to consider when pharmacologically targeting the HPA axis, as both acute and developmental effects of gonadal hormones can influence neuronal signaling in various brain regions. In Chapter 1, I investigate the effect of chronic intermittent vapor exposure to progressively increasing doses of ethanol (CIE) followed by protracted withdrawal on the physiological response to norepinephrine (NE; 10�M). I also investigate the mechanistic contributions of specific α adrenergic receptors (AR; α1AR & α2AR) on the CIE-induced neurophysiological effects. The paraventricular nucleus of the hypothalamus initiates a robust glutamate signal to start the overcome tonic GABAergic inhibition and adaptively coordinate stress-associated behaviors. We have previously shown that this metaplastic feature is disrupted in gavage models of CIE due to altered function of N-methyl D-aspartate receptor. In Chapter 2, I demonstrate that the CIEvapor model produces a similar impairment in hypothalamic metaplasticity. I also demonstrate how this effect is impacted by blockade of α1AR (with prazosin; 10�M). Astrocytes and neurons undergo a complex interplay in response to changes in the chemical gradient of various neurotransmitters. Both neurons and astrocytes have distinct responses during acute alcohol intoxication and protracted withdrawal. In Chapter 3, I investigate differences in how astrocytes and/or neurons may impact the noradrenergic activation and subsequent glucocorticoid receptor mediated inhibition of the HPA axis. The tripartite synapse is very likely involved in the regulation of stimulation-induced plasticity due to the critical role astrocytes play in glutamate shuttling, neurotransmitter release and regulation of synaptic activity. Despite this, we have not found studies evaluating the contribution of astrocytes to the metaplastic short-term glutamatergic potentiation onto CRF neurons following high-frequency stimulation. In Chapter 4, I investigate cell-specific differences to spontaneous Ca2+ events and event kinetics following CIEvapor. Various preclinical models of AUD can reliably induce anxiety-like behavior. However, AUD models fail to have full penetrance of ethanol (EtOH) preference and escalation of consumption behaviors. There are also noted genetic differences that contribute to EtOH preference. In Chapter 5, I investigate differences to stress-associated and consummatory alcohol behaviors following CIEvapor treatment. I also investigate the convergence and divergence of stress-related and consummatory behaviors with neurophysiological features of ex vivo Ca2+ signal

Chronic alcohol disrupts hypothalamic responses to stress by modifying CRF and NMDA receptor function

The chronic inability of alcoholics to effectively cope with relapse-inducing stressors has been linked to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and corticotropin-releasing factor (CRF) signaling. However, the cellular mechanisms responsible for this dysregulation are yet to be identified. After exposure of male Sprague Dawley rats to chronic intermittent ethanol (CIE; 5-6 g/kg orally for 35 doses over 50 days) or water, followed by 40-60 days of protracted withdrawal, we investigated CIE effects on glutamatergic synaptic transmission, stress-induced plasticity, CRF- and ethanol-induced NMDAR inhibition using electrophysiological recordings in parvocellular neurosecretory cells (PNCs) of the paraventricular nucleus. We also assessed CIE effects on hypothalamic mRNA expression of CRF-related genes using real-time polymerase chain reaction, and on HPA axis function by measuring stress-induced increases in plasma adrenocorticotropic hormone, corticosterone, and self-grooming. In control rats, ethanol-mediated inhibition of NMDARs was prevented by CRF1 receptor (CRFR1) blockade with antalarmin, while CRF/CRFR1-mediated NMDAR blockade was prevented by intracellularly-applied inhibitor of phosphatases PP1/PP2A, okadaic acid, but not the selective striatal-enriched tyrosine protein phosphatase inhibitor, TC-2153. CIE exposure increased GluN2B subunit-dependent NMDAR function of PNCs. This was associated with the loss of both ethanol- and CRF-mediated NMDAR inhibition, and loss of stress-induced short-term potentiation of glutamatergic synaptic inputs, which could be reversed by intracellular blockade of NMDARs with MK801. CIE exposure also blunted the hormonal and self-grooming behavioral responses to repeated restraint stress. These findings suggest a cellular mechanism whereby chronic alcohol dysregulates the hormonal and behavioral responses to repetitive stressors by increasing NMDAR function and decreasing CRFR1 function

Simultaneous monitoring of mouse grip strength, force profile, and cumulative force profile distinguishes muscle physiology following surgical, pharmacologic and diet interventions.

Grip strength is a valuable preclinical assay to study muscle physiology in disease and aging by directly determining changes in muscle force generation in active laboratory mice. Existing methods to statistically evaluate grip strength, however, have limitations in the power and scope of the physiological features that are assessed. We therefore designed a microcontroller whose serial measure of resistance-based force enables the simultaneous readout of (1) peak grip strength, (2) force profile (the non-linear progress of force exerted throughout a standard grip strength trial), and (3) cumulative force profile (the integral of force with respect to time of a single grip strength trial). We hypothesized that muscle pathologies of different etiologies have distinct effects on these parameters. To test this, we used our apparatus to assess the three muscle parameters in mice with impaired muscle function resulting from surgically induced peripheral pain, genetic peripheral neuropathy, adverse muscle effects induced by statin drug, and metabolic alterations induced by a high-fat diet. Both surgically induced peripheral nerve injury and statin-associated muscle damage diminished grip strength and force profile, without affecting cumulative force profile. Conversely, genetic peripheral neuropathy resulting from lipin 1 deficiency led to a marked reduction to all three parameters. A chronic high-fat diet led to reduced grip strength and force profile when normalized to body weight. In high-fat fed mice that were exerted aerobically and allowed to recover for 30 min, male mice exhibited impaired force profile parameters, which female mice were more resilient. Thus, simultaneous analysis of peak grip strength, force profile and cumulative force profile distinguishes the muscle impairments that result from distinct perturbations and may reflect distinct motor unit recruitment strategies

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms