Characterization of groundwater storage changes in the Amazon River Basin based on downscaling of GRACE/GRACE-FO data with machine learning models.

Groundwater storage changes in the Amazon River Basin (ARB) play an important role in the hydrological behavior of the region, with significant influence on climate variability and rainforest ecosystems. The GRACE and GRACE-FO satellite missions provide gravity anomalies from which it is possible to monitor changes in terrestrial water storage, albeit at low spatial resolution. This study downscaled GRACE and GRACE-FO data from machine learning models from 1° (110 km approx) to 0.

Descending Control of Nociception Poorly Predicts the Development of Persistent Postsurgical Pain-like Behavior in Consomic Dahl S Rat Strains.

Background: Chronic postsurgical pain is a poorly recognized outcome of surgery where patients experience pain long after healing from the surgical insult. Descending control of nociception, a phenomenon whereby application of a strong nociceptive stimulus to one part of the body of animals inhibits pain in remote body regions, offers one strategy to identify a propensity to develop chronic postsurgical pain-like behavior. Here, consomic rat panel was used to test the hypothesis that pain persistence is mechanistically linked to ineffective descending control of nociception.

Analysis and comparison of wellhead protection areas delimitation methods applying a stochastic MODFLOW model as a reference.

Sustainable use of groundwater while maintaining economic and social development is a major challenge, and the implementation of wellhead protection areas (WHPA) for public supply wells has been applied as an instrument to overcome it. This study analyzes the WHPA delineation methods: calculated fixed radius (CFR) and two solutions of the WhAEM software (USEPA, 2018), one analytical and one semi-analytical. We compare their results with WHPAs generated by a stochastic three-dimensional MODFLOW-MODPATH model in two scenarios: eight pumping wells operating simultaneously and a single well pumping, both at the same public drinking water supply wellfield located on a coastal plain in Jaguaruna County, south Brazil.

Discovering chronic pain treatments: better animal models might help us get there.

Only three classes of pain medications have made it into clinical use in the past 60 years despite intensive efforts and the need for nonaddictive pain treatments. One reason for the failure involves the use of animal models that lack mechanistic similarity to human pain conditions, with endpoint measurements that may not reflect the human pain experience. In this issue of the JCI, Ding, Fischer, and co-authors developed the foramen lacerum impingement of trigeminal nerve root (FLIT) model of human trigeminal neuralgia that has improved face, construct, and predictive validities over those of current models.

Characterization of the Dahl salt-sensitive rat as a rodent model of inherited, widespread, persistent pain.

Animal models are essential for studying the pathophysiology of chronic pain disorders and as screening tools for new therapies. However, most models available do not reproduce key characteristics of clinical persistent pain. This has limited their ability to accurately predict which new medicines will be clinically effective.

A novel rat model of temporomandibular disorder with improved face and construct validities.

Aims: Temporomandibular disorders are a cluster of orofacial conditions that are characterized by pain in the temporomandibular joint (TMJ) and surrounding muscles/tissues. Animal models of painful temporomandibular dysfunction (TMD) are valuable tools to investigate the mechanisms responsible for symptomatic temporomandibular joint and associated structures disorders. We tested the hypothesis that a predisposing and a precipitating factor are required to produce painful TMD in rats, using the ratgnawmeter, a device that determines temporomandibular pain based on the time taken for the rat to chew through two obstacles.

D2 Receptors in the Periaqueductal Gray/Dorsal Raphe Modulate Peripheral Inflammatory Hyperalgesia via the Rostral Ventral Medulla.

Dopamine neurons in the periaqueductal gray (PAG)/dorsal raphe are key modulators of antinociception with known supraspinal targets. However, no study has directly tested whether these neurons contribute to descending pain inhibition. We hypothesized that PAG dopamine neurons contribute to the analgesic effect of D-amphetamine via a mechanism that involves descending modulation via the rostral ventral medulla (RVM).

Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy.

Although clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28.

Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA.

Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE . Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood.

Marked sexual dimorphism in neuroendocrine mechanisms for the exacerbation of paclitaxel-induced painful peripheral neuropathy by stress.

Chemotherapy-induced neuropathic pain is a serious adverse effect of chemotherapeutic agents. Clinical evidence suggests that stress is a risk factor for development and/or worsening of chemotherapy-induced peripheral neuropathy (CIPN). We evaluated the impact of stress and stress axis mediators on paclitaxel CIPN in male and female rats.

Systemic Morphine Produces Dose-dependent Nociceptor-mediated Biphasic Changes in Nociceptive Threshold and Neuroplasticity.

We investigated the dose dependence of the role of nociceptors in opioid-induced side-effects, hyperalgesia and pain chronification, in the rat. Systemic morphine produced a dose-dependent biphasic change in mechanical nociceptive threshold. At lower doses (0.

Mu-opioid Receptor (MOR) Biased Agonists Induce Biphasic Dose-dependent Hyperalgesia and Analgesia, and Hyperalgesic Priming in the Rat.

Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E (PGE) produced prolonged hyperalgesia (priming).

Swedish Nerve Growth Factor Mutation (NGF) Defines a Role for TrkA and p75 in Nociception.

Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGF) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGF Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGF mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation.

Role of GPCR (mu-opioid)-receptor tyrosine kinase (epidermal growth factor) crosstalk in opioid-induced hyperalgesic priming (type II).

Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: opioid-induced hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors.

Fentanyl Induces Rapid Onset Hyperalgesic Priming: Type I at Peripheral and Type II at Central Nociceptor Terminals.

Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague Dawley rats, the effect of local administration of agents that reverse type I (protein translation) or type II [combination of Src and mitogen-activated protein kinase (MAPK)] priming. At the central terminal, priming induced by systemic, intradermal, or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, but at the peripheral terminal, it was reversed by the protein translation inhibitor.

CD44 Signaling Mediates High Molecular Weight Hyaluronan-Induced Antihyperalgesia.

We studied, in male Sprague Dawley rats, the role of the cognate hyaluronan receptor, CD44 signaling in the antihyperalgesia induced by high molecular weight hyaluronan (HMWH). Low molecular weight hyaluronan (LMWH) acts at both peptidergic and nonpeptidergic nociceptors to induce mechanical hyperalgesia that is prevented by intrathecal oligodeoxynucleotide antisense to CD44 mRNA, which also prevents hyperalgesia induced by a CD44 receptor agonist, A6. Ongoing LMWH and A6 hyperalgesia are reversed by HMWH.

Age-Dependent Sexual Dimorphism in Susceptibility to Develop Chronic Pain in the Rat.

Neonatal pain has been suggested to contribute to the development and/or persistence of adult pain. Observations from animal models have shown that neonatal inflammation produces long-term changes in sensory neuron function, which can affect the susceptibility of adults to develop persistent pain. We used a preclinical model of transition to chronic pain, hyperalgesic priming, in which a previous inflammatory stimulus triggers a long-lasting increase in responsiveness to pro-algesic mediators, prototypically prostaglandin E (PGE), to investigate if post-natal age influences susceptibility of adult rats to develop chronic pain.

Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms.

We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming.

Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP Receptors in the Induction of Hyperalgesic Priming.

Hyperalgesic priming, a model of pain chronification in the rat, is mediated by ryanodine receptor-dependent calcium release. Although ryanodine induces priming in both sexes, females are 5 orders of magnitude more sensitive, by an estrogen receptor α (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP) receptor inhibitor prevented the induction of priming by ryanodine.

Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor α in the Rat.

Unlabelled: Hyperalgesic priming, a sexually dimorphic model of transition to chronic pain, is expressed as prolongation of prostaglandin E2-induced hyperalgesia by the activation of an additional pathway including an autocrine mechanism at the plasma membrane. The autocrine mechanism involves the transport of cyclic adenosine monophosphate (AMP) to the extracellular space, and its conversion to AMP and adenosine, by ecto-5'phosphodiesterase and ecto-5'nucleotidase, respectively. The end product, adenosine, activates A1 receptors, producing delayed onset prolongation of prostaglandin E2 hyperalgesia.

Marked sexual dimorphism in 5-HT receptors mediating pronociceptive effects of sumatriptan.

Amongst the side effects of triptans, a substantial percentage of patients experience injection site pain and tenderness, the underlying mechanism of which is unknown. We found that the dose range from 10fg to 1000ng (intradermal) of sumatriptan induced a complex dose-dependent mechanical hyperalgesia in male rats, with distinct peaks, at 1pg and 10ng, but no hyperalgesia at 1ng. In contrast, in females, there was 1 broad peak.

Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat.

Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKCε), occurs in male but not in female rats. However, activation of second messengers downstream of PKCε, such as the ryanodine receptor, induces priming in both sexes. Since estrogen regulates intracellular calcium, we investigated the interaction between estrogen and ryanodine in the susceptibility to develop priming in females.

Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.

We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming.

Adenosine-A1 receptor agonist induced hyperalgesic priming type II.

We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent.

Contribution of Piezo2 to endothelium-dependent pain.

Background: We evaluated the role of a mechanically-gated ion channel, Piezo2, in mechanical stimulation-induced enhancement of hyperalgesia produced by the pronociceptive vasoactive mediator endothelin-1, an innocuous mechanical stimulus-induced enhancement of hyperalgesia that is vascular endothelial cell dependent. We also evaluated its role in a preclinical model of a vascular endothelial cell dependent painful peripheral neuropathy.

Results: The local administration of oligodeoxynucleotides antisense to Piezo2 mRNA, at the site of nociceptive testing in the rat's hind paw, but not intrathecally at the central terminal of the nociceptor, prevented innocuous stimulus-induced enhancement of hyperalgesia produced by endothelin-1 (100 ng).