GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior

Diabetes

2022 May 02

Samms, RJ;Cosgrove, R;Snider, BM;Furber, EC;Droz, BA;Briere, DA;Dunbar, J;Dogra, M;Alsina-Fernandez, J;Borner, T;De Jonghe, BC;Hayes, MR;Coskun, T;Sloop, KW;Emmerson, PJ;Ai, M;
PMID: 35499381 | DOI: 10.2337/db21-0848

The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of Peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist (GIPRA) reduced conditioned taste avoidance (CTA) without affecting hypophagia induced by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in the detection of aversive stimuli. Peripheral administration of a GIPRA induced neuronal activation (cFOS) in the AP. Further, whole-brain cFOS analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), an area of the brain that relays aversive/emetic stimuli to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPRA treatment reduces PYY-induced nausea-like behavior. Together, our study provides a novel mechanism by which GIP-based therapeutics may benefit the tolerability of weight loss agents.

A basomedial amygdala to intercalated cells microcircuit expressing PACAP and its receptor PAC1 regulates contextual fear

The Journal of neuroscience : the official journal of the Society for Neuroscience

2021 Feb 26

Rajbhandari, AK;Octeau, JC;Gonzalez, S;Pennington, ZT;Mohamed, F;Trott, J;Chavez, J;Ngyuen, E;Keces, N;Hong, WZ;Neve, RL;Waschek, J;Khakh, BS;Fanselow, MS;
PMID: 33637560 | DOI: 10.1523/JNEUROSCI.2564-20.2021

Trauma can cause dysfunctional fear regulation leading some people to develop disorders such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased cfos expression in mICCs, decreased fear recall and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICCs PACAPergic pathway produced excitatory postsynaptic currents (EPSCs) in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENTTraumatic stress can affect different aspects of fear behaviors including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear including acquisition, generalization, recall and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.

Selectively inhibiting the median preoptic nucleus attenuates angiotensin II and hyperosmotic-induced drinking behavior and vasopressin release in adult male rats.

eNeuro

2019 Mar 07

Marciante AB, Wang LA, Farmer GE, Cunningham JT.
PMID: - | DOI: 10.1523/ENEURO.0473-18.2019

The median preoptic nucleus (MnPO) is a putative integrative region that contributes to body fluid balance. Activation of the MnPO can influence thirst but it is not clear how these responses are linked to body fluid homeostasis. We used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to determine the role of the MnPO in drinking behavior and vasopressin release in response to peripheral angiotensin II (ANG II) or 3% hypertonic saline in adult male Sprague-Dawley rats (250-300g). Rats were anesthetized with isoflurane and stereotaxically injected with an inhibitory DREADD (rAAV5-CaMKIIa-hM4D(Gi)-mCherry) or control (rAAV5-CaMKIIa-mCherry) virus in the MnPO. After 2 weeks’ recovery, a subset of rats were used for extracellular recordings to verify functional effects of ANG II or hyperosmotic challenges in MnPO slice preparations. Remaining rats were used in drinking behavior studies. Each rat was administered either 10mg/kg of exogenous clozapine-N-oxide (CNO) to inhibit DREADD-expressing cells or vehicle ip followed by a test treatment with either 2mg/kg ANG II or 3% hypertonic saline (1mL/100g bw) sc, twice per week for two separate treatment weeks. CNO-induced inhibition during either test treatment significantly attenuated drinking responses compared to vehicle treatments and controls. Brain tissue processed for cFos immunohistochemistry showed decreased expression with CNO-induced inhibition during either test treatment in the MnPO and downstream nuclei compared to controls. CNO-mediated inhibition significantly attenuated treatment-induced increases in plasma vasopressin compared to controls. The results indicate inhibition of CaMKIIa-expressing MnPO neurons significantly reduces drinking and vasopressin release in response to ANG II or hyperosmotic challenge.

Significance Statement The MnPO is an important regulatory center that influences thirst, cardiovascular and neuroendocrine function. Activation of different MnPO neuronal populations can inhibit or stimulate water intake. However, the role of the MnPO and its pathway-specific projections during ANG II and hyperosmotic challenges still have not yet been fully elucidated. These studies directly address this by using DREADDs to acutely and selectively inhibit pathway-specific MnPO neurons, and uses techniques that measure changes at the protein, neuronal, and overall physiological and behavioral level. More importantly, we have been able to demonstrate that physiological challenges related to extracellular (ANG II) or cellular (hypertonic saline) dehydration activate MnPO neurons that may project to different parts of the hypothalamus.

TRPM3 channels play roles in heat hypersensitivity and spontaneous pain after nerve injury

The Journal of neuroscience : the official journal of the Society for Neuroscience

2021 Jan 15

Su, S;Yudin, Y;Kim, N;Tao, YX;Rohacs, T;
PMID: 33478988 | DOI: 10.1523/JNEUROSCI.1551-20.2020

Transient Receptor Potential Melastatin 3 (TRPM3) is a heat-activated ion channel in primary sensory neurons of the dorsal root ganglia (DRG). Pharmacological and genetic studies implicated TRPM3 in various pain modalities, but TRPM3 inhibitors were not validated in TRPM3-/- mice. Here we tested two inhibitors of TRPM3 in male and female wild type and TRPM3-/- mice in nerve injury-induced neuropathic pain. We found that intraperitoneal injection of either isosakuranetin, or primidone reduced heat hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve, in wild type, but not in TRPM3-/- mice. Primidone was also effective when injected locally in the hind paw, or intrathecally. Consistently, intrathecal injection of the TRPM3 agonist CIM0216 reduced paw withdrawal latency to radiant heat in wild type, but not in TRPM3-/- mice. Intraperitoneal injection of 2 mg/kg, but not 0.5 mg/kg isosakuranetin, inhibited cold and mechanical hypersensitivity in CCI, both in wild-type and TRPM3-/- mice, indicating a dose dependent off target effect. Primidone had no effect on cold sensitivity, and only a marginal effect on mechanical hypersensitivity. Genetic deletion or inhibitors of TRPM3 reduced the increase in the levels of the early genes cFos and pERK in the spinal cord and DRG in CCI mice, suggesting spontaneous activity of the channel. Intraperitoneal isosakuranetin also inhibited spontaneous pain related behavior in CCI in the conditioned place preference assay, and this effect was eliminated in TRPM3-/- mice. Overall our data indicate a role of TRPM3 in heat hypersensitivity and in spontaneous pain after nerve injury.SIGNIFICANCE STATEMENT:Neuropathic pain is a major unsolved medical problem. The heat-activated TRPM3 ion channel is a potential target for novel pain medications, but it is not clear what pain modalities it plays roles in. Here we used a combination of genetic and pharmacological tools to assess the role of this channel in spontaneous pain, heat-, cold- and mechanical hypersensitivity in a nerve injury model of neuropathic pain in mice. Our findings indicate a role for TRPM3 in heat hyperalgesia, and spontaneous pain, but not in cold, and mechanical hypersensitivity. We also find that not only TRPM3 located in the peripheral nerve termini, but also TRPM3 in the spinal cord, or proximal segments of DRG neurons is important for heat hypersensitivity.

Effects of Post Trauma Morphine On Dorsal Horn Neuron Excitability: Studies using cFOS and RNAscope

University of Colorado Honors Journal

2023 May 04

Woodall, B;
| DOI: 10.33011/cuhj20231847

Previous research has shown that a 5-day course of morphine enhances nociceptive sensitivity and allodynia when given 10 days after chronic constriction injury (CCI) as measured by the Von Frey test, a test where the hindpaw is poked with force (measured in grams) calibrated filament. This increased sensitivity to touch suggests that post trauma morphine makes second order sensory dorsal horn neurons more excitable. Therefore, it is hypothesized that during morphine enhanced allodynia, dorsal horn neurons will be more excitable to nociceptive stimulus. It was found that morphine enhanced allodynia causes more excitable neurons across a larger spatial range of the spinal cord, both rostral-caudal and dorsal-ventral along the dorsal horn. Mechanisms for the increased excitability of the dorsal horn are proposed and explored. These findings add to a robust literature which has detailed the paradoxical pain amplifying effects of morphine. Further, this study predicts that hyperexcitability of pain and touch pathways may occur as a clinically unintended side effect of morphine when administered to treat ongoing neuropathic pain. Lay Summary When working on the body, opioids take effect on various cells- including cells of the nervous system known as Glia. These glial cells produce various inflammatory responses that are typically known to decrease inflammation in the body. However, prior literature has revealed that following an activated state, these cells enter a “primed” form. If a second immunological activation occurs during this primed state, glial cells have been shown to release proteins that actually potentiate the state of pain. This study examines this hypothesis through the context of peripheral nerve injury (modeling injury, surgery, or trauma), followed by an administration of morphine. Using advanced imaging techniques, we are able to visualize exactly what modulators are inducing this potentiated pain response, as well as where in the nervous system these cells are found. Morphine has a potent effect on various aspects of the nervous system which may be alleviated by other treatment routes that focus specifically on the cell type and location that release the molecules that initiate the healing process. By unveiling the details of this mechanism, we can better understand how to treat patients following injury or surgery without inducing a higher pain response that can be caused by a short-term administration of morphine. To see the complete thesis, please visit https://scholar.colorado.edu/concern/undergraduate_honors_theses/0k225c53t.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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