Expression and Pharmacological Modulation of Pain-Depressed Behavior in Rats

Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This goal of this dissertation was to conduct preclinical research experiments designed to address a set of three inter-related aims that examine the expression, mechanisms and treatment of pain-related depression of Intracranial Self-Stimulation (ICSS) in rats. First, studies evaluated the hypothesis that acute acid-induced depression of ICSS was mediated by a kappa opioid receptor mediated decrease in mesolimbic dopamine release in the nucleus accumbens. Results support a role for depressed mesolimbic dopamine release in pain-related depression of ICSS; however, a role for kappa opioid receptors is not supported. Second, studies evaluated the effectiveness of a more sustained inflammatory noxious stimulus (intraplantar CFA) and a sustained neuropathic stimulus (intraplantar formalin) to produce a long-term pain-related depression of ICSS, and the role of kappa opioid receptors in mediating this sustained pain-related depression of ICSS. Results indicated that only the neuropathic stimulus (formalin) was sufficient to produce sustained depression of ICSS, and as in the initial studies, our data did not support a role for kappa receptors in mediating this effect. Given the poor effectiveness of a kappa receptor antagonist to block acute or chronic pain-related depression of ICSS, the final set of studies evaluated the pharmacology of representative drugs from five different classes of established or candidate analgesics (mu opioid agonists, non-steroidal anti-inflammatory drugs, monoamine uptake inhibitors, anticonvulsants, and cannabinoid agonists) to reverse the sustained depression of ICSS produced by formalin as a neuropathic stimulus. Results demonstrate the mu agonist morphine, the monoamine uptake inhibitor bupropion, the anticonvulsant gabapentin, and the cannabinoid agonist THC were able to reverse formalin-induced mechanical allodynia as a pain-stimulated behavior, but only the mu agonist morphine and the monoamine uptake inhibitor bupropion were effective to reverse formalin-induced depression of ICSS. These results provided additional evidence for dissociable drug effects in preclinical assays of pain-stimulated and pain-depressed behavior and also support further studies with monoamine uptake inhibitors with a dopaminergic component (like bupropion) for treatment of neuropathic pain

Effects of Acute and Sustained Pain Manipulations on Performance in a Visual‐Signal Detection Task of Attention in Rats

Preclinical ResearchPatients with pain often display cognitive impairment including deficits in attention. The visual‐signal detection task (VSDT) is a behavioral procedure for assessment of attention in rodents. Male Sprague Dawley rats were trained in a VSDT and tested with three different noxious stimuli: (i) intraperitoneal injection of lactic acid; (ii) intraplantar injection of formalin; and (iii) intraplantar injection of complete Freund's adjuvant (CFA). The muscarinic acetylcholine receptor antagonist, scopolamine was also tested as a positive control. Scopolamine (0.01–1.0 mg/kg) dose dependently reduced accuracy and increased response latencies during completed trials with higher scopolamine doses increasing omissions. Lactic acid (0.56–5.6% ip) also increased response latencies and omissions, although it failed to alter measures of response accuracy. Formalin produced a transient decrease in accuracy while also increasing both response latency and omissions. CFA failed to alter VSDT performance. Although VSDT effects were transient for formalin and absent for CFA, both treatments produced mechanical allodynia and paw edema for up to 7 days. These results support the potential for noxious stimuli to produce a pain‐related disruption of attention in rats. However, relatively strong noxious stimulation appears necessary to disrupt performance in this version of the VSDT. Drug Dev Res 76 : 194–203, 2015. © 2015 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111955/1/ddr21255.pd

Sustained pain-related depression of behavior: effects of intraplantar formalin and complete freund’s adjuvant on intracranial self-stimulation (ICSS) and endogenous kappa opioid biomarkers in rats

Background: Intraplantar administration of complete Freund's adjuvant (CFA) and formalin are two noxious stimuli commonly used to produce sustained pain-related behaviors in rodents for research on neurobiology and treatment of pain. One clinically relevant manifestation of pain is depression of behavior and mood. This study compared effects of intraplantar CFA and formalin on depression of positively reinforced operant behavior in an assay of intracranial self-stimulation (ICSS) in rats. Effects of CFA and formalin on other physiological and behavioral measures, and opioid effects on formalin-induced depression of ICSS, were also examined. Results: There were four main findings. First, consistent with previous studies, both CFA and formalin produced similar paw swelling and mechanical hypersensitivity. Second, CFA produced weak and transient depression of ICSS, whereas formalin produced a more robust and sustained depression of ICSS that lasted at least 14 days. Third, formalin-induced depression of ICSS was reversed by morphine doses that did not significantly alter ICSS in saline-treated rats, suggesting that formalin effects on ICSS can be interpreted as an example of pain-related and analgesic-reversible depression of behavior. Finally, formalin-induced depression of ICSS was not associated with changes in central biomarkers for activation of endogenous kappa opioid systems, which have been implicated in depressive-like states in rodents, nor was it blocked by the kappa antagonist norbinaltorphimine. Conclusions: These results suggest differential efficacy of sustained pain stimuli to depress brain reward function in rats as assessed with ICSS. Formalin-induced depression of ICSS does not appear to engage brain kappa opioid systems. Electronic supplementary material The online version of this article (doi:10.1186/1744-8069-10-62) contains supplementary material, which is available to authorized users

Search for Axionlike Particles Produced in e⁺ e⁻ Collisions at Belle II

International audienceWe present a search for the direct production of a light pseudoscalar a decaying into two photons with the Belle II detector at the SuperKEKB collider. We search for the process e+e-→γa, a→γγ in the mass range 0.2

Measurement of Hadronic Mass Moments ⟨MXn⟩\langle M_X^n \rangle in B→Xcℓνℓ B \rightarrow X_c \ell \nu_\ell\ Decays at Belle II

We present measurements of the first six hadronic mass moments in semileptonic $B \rightarrow X_c \ell \nu_\ell\$ decays. The hadronic mass moments, together with other observables of inclusive $B$ decays, can be used to determine the CKM matrix element $|{V_{cb}}|$ and mass of the $b$-quark $m_b$ in the context of Heavy Quark Expansions of QCD. The Belle~II data recorded at the $\Upsilon (4S)$ resonance in 2019 and 2020 (March-July), corresponding to an integrated luminosity of $34.6\;\mathrm{fb}^{-1}$, is used for this measurement. The decay $\Upsilon (4S) \rightarrow B \overline{B}$ is reconstructed by applying the hadronic tagging algorithm provided by the Full Event Interpretation to fully reconstruct one $B$ meson. The second $B$ meson is reconstructed inclusively by selecting a high-momentum lepton. The $X_c$ system is identified by the remaining reconstructed tracks and clusters in the electromagnetic calorimeter. We report preliminary results for the hadronic mass moments $\langle M_X^n \rangle$ with $n=1,\dots,6$, measured as a function of a lower cut on the lepton momentum in the signal $B$ rest frame