Enhancing Chronic Non-Cancer Pain Management: A Systematic Review of Mindfulness Therapies and Guided Imagery Interventions.

Background and Objectives: There has been an increasing interest in the use of non-pharmacological approaches for the multidimensional treatment of chronic pain. The aim of this systematic review was to assess the effectiveness of mindfulness-based therapies and Guided Imagery (GI) interventions in managing chronic non-cancer pain and related outcomes. Materials and Methods: Searching three electronic databases (Web of Science, PubMed, and Scopus) and following the PRISMA guidelines, a systematic review was performed on Randomized Controlled Trials (RCTs) and pilot RCTs investigating mindfulness or GI interventions in adult patients with chronic non-cancer pain. The Cochrane Risk of Bias Tool was utilized to assess the quality of the evidence, with outcomes encompassing pain intensity, opioid consumption, and non-sensorial dimensions of pain. Results: Twenty-six trials met the inclusion criteria, with most of them exhibiting a moderate to high risk of bias. A wide diversity of chronic pain types were under analysis. Amongst the mindfulness interventions, and besides the classical programs, Mindfulness-Oriented Recovery Enhancement (MORE) emerges as an approach that improves interoception. Six trials demonstrated that mindfulness techniques resulted in a significant reduction in pain intensity, and three trials also reported significant outcomes with GI. Evidence supports a significant improvement in non-sensory dimensions of pain in ten trials using mindfulness and in two trials involving GI. Significant effects on opioid consumption were reported in four mindfulness-based trials, whereas one study involving GI found a small effect with that variable. Conclusions: This study supports the evidence of benefits of both mindfulness techniques and GI interventions in the management of chronic non-cancer pain. Regarding the various mindfulness interventions, a specific emphasis on the positive results of MORE should be highlighted. Future studies should focus on specific pain types, explore different durations of the mindfulness and GI interventions, and evaluate emotion-related outcomes.

Perceptions of medical students towards the role of histology and embryology during curricular review.

BACKGROUND: The continuous changes in the medical education to prepare medical doctors for the future requires updates in medical curriculum. However, the perspectives of the medical students are not frequently considered during the revision of the medical curriculum. In parallel with the process of defining and adjusting the medical curriculum, a large survey was performed to inquire the perspectives of the medical students at the Faculty of Medicine of the University of Porto (FMUP), Portugal, about the role of Histology and of Embryology. METHODS: Medical students at FMUP (Portugal) completed a structured and anonymous online questionnaire about the subjects Histology and Embryology. The questionnaire was prepared using questions of previous surveys performed in Europe, including another Portuguese medical school, and additional questions that were specifically prepared to this study. The questions referred to teaching methods, clinical relevance, use of virtual (digital) microscopes and association of Histology and Embryology with other subjects of the medical curriculum. RESULTS: Four hundred and sixty-two students participated in the study. The students in clinical years were more likely to recognise the clinical relevance of Histology (p = 0.016) and Embryology (p < 0.001). Students agree that teaching of these subjects would benefit from a clinical orientation (89% for Histology; 90% for Embryology). Students highlighted that Histology is crucial to understand Biopathology and agree (75%) that an integration of Histology with Biopathology could be considered in the medical curriculum. Most students (55%) agree that slide microscopes are more useful than virtual microscopes. CONCLUSIONS: Our study contributes to the debate about the evolution of medical curriculum. Gathering the medical students' perceptions using large surveys such as that performed in the present study may be useful to adapt the methods of teaching which may increase the motivation of the students. In the case of Histology and Embryology at the FMUP (Portugal) providing more clinically oriented teaching may be useful to motivate the students. Students of clinical years have strong clinical perspectives of Histology and Embryology and their enrolment in teaching of Histology and Embryology can also contribute to increase motivation of younger students. Consulting and involving medical students in the development of the medical curriculum can be positive and students should be more responsible and engaged in building their own education.

Spinal Cord Injury and Complications Related to Neuraxial Anaesthesia Procedures: A Systematic Review.

The use of neuraxial procedures, such as spinal and epidural anaesthesia, has been linked to some possible complications. In addition, spinal cord injuries due to anaesthetic practice (Anaes-SCI) are rare events but remain a significant concern for many patients undergoing surgery. This systematic review aimed to identify high-risk patients summarise the causes, consequences, and management/recommendations of SCI due to neuraxial techniques in anaesthesia. A comprehensive search of the literature was conducted in accordance with Cochrane recommendations, and inclusion criteria were applied to identify relevant studies. From the 384 studies initially screened, 31 were critically appraised, and the data were extracted and analysed. The results of this review suggest that the main risk factors reported were extremes of age, obesity, and diabetes. Anaes-SCI was reported as a consequence of hematoma, trauma, abscess, ischemia, and infarction, among others. As a result, mainly motor deficits, sensory loss, and pain were reported. Many authors reported delayed treatments to resolve Anaes-SCI. Despite the potential complications, neuraxial techniques are still one of the best options for opioid-sparing pain prevention and management, reducing patients' morbidity, improving outcomes, reducing the length of hospital stay, and pain chronification, with a consequent economic benefit. The main findings of this review highlight the importance of careful patient management and close monitoring during neuraxial anaesthesia procedures to minimise the risk of spinal cord injury and complications.

Pharmacological modulation of ventral tegmental area neurons elicits changes in trigeminovascular sensory processing and is accompanied by glycemic changes: Implications for migraine.

BACKGROUND: Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients. METHODS: Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection. RESULTS: Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels. CONCLUSION: Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.

Pain Modulation from the Locus Coeruleus in a Model of Hydrocephalus: Searching for Oxidative Stress-Induced Noradrenergic Neuroprotection.

Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-ß-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation.

Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy-induced neuropathy: The role of spinal 5-HT3 receptors.

Chemotherapy-induced neuropathy (CIN) is a common complication of cancer treatment. Although CIN is treated with antidepressants that act at serotonin (5-HT) reuptake, the mechanisms of serotoninergic modulation of nociceptive transmission during CIN remain unknown, namely as to the involvement of the rostroventromedial medulla (RVM) and the role of spinal 5-HT3 receptors (5-HT3R). Male Wistar rats were injected with the cytostatic paclitaxel or vehicle solution. One month after CIN induction, we first studied the activation of RVM neurons, and then the activation of the local serotoninergic neurons. Immunostaining of phosphorylated extracellular signal-regulated kinase (pERK) indicated increased activation in paclitaxel-injected animals. The double immunohistochemistry of pERK and tryptophan hydroxylase (TpH) showed higher expression of TpH and increased co-localization of TpH and pERK of paclitaxel-injected animals, indicating that CIN is associated with increased activation of serotoninergic RVM neurons. The 5-HT content at the spinal dorsal horn assessed by HPLC was higher in paclitaxel-injected animals. The immunohistochemical analysis of 5-HT also showed increased expression at the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The levels of 5-HT3R detected by immunohistochemistry were higher in the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The intrathecal administration of the 5-HT3R antagonist ondansetron reversed mechanical and cold hypersensitivity in the von Frey and cold plate tests, respectively. The results indicate that CIN is associated with increased recruitment of descending 5-HT-mediated modulation from the RVM which affects the spinal serotoninergic system and probably accounts for pain hypersensitivity due to the pronociceptive role of spinal 5-HT3R.

Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats.

BACKGROUND: Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling. METHODS: The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling. The authors used pharmacologic and gene-mediated approaches. Nociceptive behaviors were evaluated by the von Frey and hot-plates tests. RESULTS: Lidocaine fully reversed mechanical and thermal hypersensitivity induced by chronic morphine. Morphine-infusion increased µ-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. µ-opioid receptor knockdown in morphine-infused animals attenuated the decrease of mechanical thresholds and heat-evoked withdrawal latencies compared with the control vector (von Frey [mean ± SD]: -17 ± 8% vs. -40 ± 9.0%; P < 0.001; hot-plate: -10 ± 5% vs. -32 ± 10%; P = 0.001). µ-opioid receptor knockdown in control animals induced the opposite (von Frey: -31 ± 8% vs. -17 ± 8%; P = 0.053; hotplate: -24 ± 6% vs. -3 ± 10%; P = 0.001). The µ-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heat-evoked withdrawal latencies in morphine-infused animals. In control animals, DAMGO increased both mechanical thresholds and heat-evoked withdrawal latencies. Ultra-low-dose naloxone, which prevents the excitatory signaling of the µ-opioid receptor, administered alone, attenuated mechanical and thermal hypersensitivities, and coadministered with DAMGO, restored DAMGO analgesic effects and decreased phosphorylated cAMP response element-binding levels. CONCLUSIONS: Chronic morphine shifted µ-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat.

Neuroendocrine signaling modulates specific neural networks relevant to migraine.

Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10U·kg-1), glucagon (100µg·200µl-1) and leptin (0.3, 1 and 3mg·kg-1) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (p<0.001) and leptin (p<0.01) whereas glucagon had the opposite effect (p<0.001). Dural-evoked neuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (p<0.001), glucagon (p<0.05) and leptin (p<0.01). Trigeminocervical-complex pERK1/2 cell expression was significantly decreased by insulin and leptin (both p<0.001), and increased by glucagon (p<0.001), when compared to vehicle control. However, only leptin affected pERK1/2 expression in the hypothalamus, significantly decreasing pERK1/2 immunoreactive cell expression in the arcuate nucleus (p<0.05). These findings demonstrate that insulin, glucagon and leptin can alter the transmission of trigeminal nociceptive inputs. A potential neurobiological link between migraine and impaired metabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction.

Pain modulation from the brain during diabetic neuropathy: Uncovering the role of the rostroventromedial medulla.

Diabetic neuropathy has a profound impact in the quality of life of patients who frequently complain of pain. The mechanisms underlying diabetic neuropathic pain (DNP) are no longer ascribed only to damage of peripheral nerves. The effects of diabetes at the central nervous system are currently considered causes of DPN. Management of DNP may be achieved by antidepressants that act on serotonin (5-HT) uptake, namely specific serotonin reuptake inhibitors. The rostroventromedial medulla (RVM) is a key pain control center involved in descending pain modulation at the spinal cord through local release of 5-HT and plays a peculiar role in the balance of bidirectional control (i.e. inhibitory and facilitatory) from the brain to the spinal cord. This review discusses recently uncovered neurobiological mechanisms that mediate nociceptive modulation from the RVM during diabetes installation. In early phases of the disease, facilitation of pain modulation from the RVM prevails through a triplet of mechanisms which include increase in serotonin expression at the RVM and consequent rise of serotonin levels at the spinal cord and upregulation of local facilitatory 5HT3 receptors, enhancement of spontaneous activity of facilitatory RVM neurons and up-regulation of the expression of transient receptor potential vanilloid type 1 (TRPV1) receptor. With the progression of diabetes the alterations in the RVM increase dramatically, with oxidative stress and neuronal death associated to microglia-mediated inflammation. In a manner similar to other central areas, like the thalamus, the RVM is likely to be a "pain generator/amplifier" during diabetes, accounting to increase DNP. Early interventions in DNP prevention using strategies that simultaneously tackle the exacerbation of 5-HT3 spinal receptors and of microglial RVM activity, namely those that increase the levels of anti-inflammatory cytokines, should be considered in the future of DNP treatment.

Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives.

Amidated kyotorphin (L-Tyr-L-Arg-NH2; KTP-NH2) causes analgesia when systemically administered. The lipophilic ibuprofen-conjugated derivative of KTP-NH2 has improved analgesic efficacy. However, fast degradation by peptidases impacts negatively in the pharmacodynamics of these drugs. In this work, selected derivatives of KTP and KTP-NH2 were synthesized to combine lipophilicity and resistance to enzymatic degradation. Eight novel structural modifications were tested for the potential to transverse lipid membranes and to evaluate their efficacy in vivo. The rationale behind the design of the pool of the eight selected molecules consisted in the addition of individual group at the N-terminus, namely the tert-butyloxycarbonyl (Boc), γ-aminobutyric acid (GABA), acetyl, butanoyl, and propanoyl or in the substitution of the tyrosine residue by an indole moiety and in the replacement of the peptidic bond by a urea-like bond in some cases. All the drugs used in the study are intrinsically fluorescent, which enables the use of spectrofluorimetry to sample the drugs in the permeation assays. The results show that the BOC and indolyl derivatives of KTP-NH2 have maximal ability to permeate membranes with concomitant maximal analgesic power. Overall, the results demonstrate that membrane permeation is correlated with analgesic efficacy. However, this is not the only factor accounting for analgesia. KTP-NH2 for instance has low passive permeation but is known to have central action. In this case, hypothetical transcytosis over the blood-brain barrier seems to depend on dipeptide transporters.

Increased noradrenergic neurotransmission to a pain facilitatory area of the brain is implicated in facilitation of chronic pain.

BACKGROUND: Noradrenaline reuptake inhibitors are known to produce analgesia through a spinal action but they also act in the brain. However, the action of noradrenaline on supraspinal pain control regions is understudied. The authors addressed the noradrenergic modulation of the dorsal reticular nucleus (DRt), a medullary pronociceptive area, in the spared nerve injury (SNI) model of neuropathic pain. METHODS: The expression of the phosphorylated cAMP response element-binding protein (pCREB), a marker of neuronal activation, was evaluated in the locus coeruleus and A5 noradrenergic neurons (n = 6 rats/group). pCREB was studied in noradrenergic DRt-projecting neurons retrogradely labeled in SNI animals (n = 3). In vivo microdialysis was used to measure noradrenaline release in the DRt on nociceptive stimulation or after DRt infusion of clonidine (n = 5 to 6 per group). Pharmacology, immunohistochemistry, and western blot were used to study α-adrenoreceptors in the DRt (n = 4 to 6 per group). RESULTS: pCREB expression significantly increased in the locus coeruleus and A5 of SNI animals, and most noradrenergic DRt-projecting neurons expressed pCREB. In SNI animals, noradrenaline levels significantly increased on pinprick (mean ± SD, 126 ± 14%; P = 0.025 vs. baseline) and acetone stimulation (mean ± SD, 151 ± 12%; P < 0.001 vs. baseline), and clonidine infusion showed decreased α2-mediated inhibitory function. α1-adrenoreceptor blockade decreased nociceptive behavioral responses in SNI animals. α2-adrenoreceptor expression was not altered. CONCLUSIONS: Chronic pain induces brainstem noradrenergic activation that enhances descending facilitation from the DRt. This suggests that antidepressants inhibiting noradrenaline reuptake may enhance pain facilitation from the brain, counteracting their analgesic effects at the spinal cord.

Transcranial Magnetic Stimulation to Treat Neuropathic Pain: A Bibliometric Analysis.

Neuropathic pain is caused by a lesion or disease of the somatosensory system and is one of the most incapacitating pain types, representing a significant non-met medical need. Due to the increase in research in the field and since innovative therapeutic strategies are required, namely in intractable neuropathic pain, neurostimulation has been used. Within this approach, transcranial magnetic stimulation (TMS) that uses a transient magnetic field to produce electrical currents over the cortex emerges as a popular method in the literature. Since this is an area in expansion and due to the putative role of TMS, we performed a bibliometric analysis in Scopus with the primary objective of identifying the scientific production related to the use of TMS to manage neuropathic pain. The research had no restrictions, and the analysis focused on the characteristics of the literature retrieved, scientific collaboration and main research topics from inception to 6 July 2023. A total of 474 articles were collected. A biggest co-occurrence between the terms "neuropathic pain" and "transcranial magnetic stimulation" was obtained. The journal "Clinical Neurophysiology" leads the Top 5 most productive sources. The United States is the most productive country, with 50% of US documents being "review articles", followed by France, with 56% of French documents being "original articles". Lefaucheur, JP and Saitoh, Y are the two most influential authors. The most frequent type of document was "original article". Most of the studies (34%) that identified the neuropathic pain type focused on traumatic neuropathic pain, although a large proportion (38%) did not report the neuropathic pain type. This study allows us to provide a general overview of the field of TMS application for neuropathic pain and is useful for establishing future directions of research in this field.

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain.

ABSTRACT: Brainstem areas involved in descending pain modulation are crucial for the analgesic actions of opioids. However, the role of opioids in these areas during tolerance, opioid-induced hyperalgesia (OIH), and in chronic pain settings remains underappreciated. We conducted a revision of the recent studies performed in the main brainstem areas devoted to descending pain modulation with a special focus on the medullary dorsal reticular nucleus (DRt), as a distinctive pain facilitatory area and a key player in the diffuse noxious inhibitory control paradigm. We show that maladaptive processes within the signaling of the µ-opioid receptor (MOR), which entail desensitization and a switch to excitatory signaling, occur in the brainstem, contributing to tolerance and OIH. In the context of chronic pain, the alterations found are complex and depend on the area and model of chronic pain. For example, the downregulation of MOR and δ-opioid receptor (DOR) in some areas, including the DRt, during neuropathic pain likely contributes to the inefficacy of opioids. However, the upregulation of MOR and DOR, at the rostral ventromedial medulla, in inflammatory pain models, suggests therapeutic avenues to explore. Mechanistically, the rationale for the diversity and complexity of alterations in the brainstem is likely provided by the alternative splicing of opioid receptors and the heteromerization of MOR. In conclusion, this review emphasizes how important it is to consider the effects of opioids at these circuits when using opioids for the treatment of chronic pain and for the development of safer and effective opioids.

Molecular targets in bone cancer pain: a systematic review of inflammatory cytokines.

Bone cancer pain (BCP) profoundly impacts patient's quality of life, demanding more effective pain management strategies. The aim of this systematic review was to investigate the role of inflammatory cytokines as potential molecular targets in BCP. A systematic search for animal rodent models of bone cancer pain studies was conducted in PubMed, Scopus, and Web of Science. Methodological quality and risk of bias were assessed using the SYRCLE RoB tool. Twenty-five articles met the inclusion criteria, comprising animal studies investigating molecular targets related to inflammatory cytokines in BCP. A low to moderate risk of bias was reported. Key findings in 23 manuscripts revealed upregulated classic pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, IL-18, IL-33) and chemokines in the spinal cord, periaqueductal gray, and dorsal root ganglia. Interventions targeting these cytokines consistently mitigated pain behaviors. Additionally, it was demonstrated that glial cells, due to their involvement in the release of inflammatory cytokines, emerged as significant contributors to BCP. This systematic review underscores the significance of inflammatory cytokines as potential molecular targets for alleviating BCP. It emphasizes the promise of targeted interventions and advocates for further research to translate these findings into effective therapeutic strategies. Ultimately, this approach holds the potential to enhance the patient's quality of life.

Noradrenergic Pathways Involved in Micturition in an Animal Model of Hydrocephalus-Implications for Urinary Dysfunction.

Hydrocephalus is characterized by enlargement of the cerebral ventricles, accompanied by distortion of the periventricular tissue. Patients with hydrocephalus usually experience urinary impairments. Although the underlying etiology is not fully described, the effects of hydrocephalus in the neuronal network responsible for the control of urination, which involves periventricular areas, including the periaqueductal gray (PAG) and the noradrenergic locus coeruleus (LC). In this study, we aimed to investigate the mechanisms behind urinary dysfunction in rats with kaolin-induced hydrocephalus. For that purpose, we used a validated model of hydrocephalus-the rat injected with kaolin in the cisterna magna-also presents urinary impairments in order to investigate the putative involvement of noradrenergic control from the brain to the spinal cord Onuf's nucleus, a key area in the motor control of micturition. We first evaluated bladder contraction capacity using cystometry. Since our previous characterization of the LC in hydrocephalic animals showed increased levels of noradrenaline, we then evaluated the noradrenergic innervation of the spinal cord's Onuf's nucleus by measuring levels of dopamine ß-hydroxylase (DBH). We also evaluated the expression of the c-Fos protooncogene, the most widely used marker of neuronal activation, in the ventrolateral PAG (vlPAG), an area that plays a major role in the control of urination by its indirect control of the LC via pontine micturition center. Hydrocephalic rats showed an increased frequency of bladder contractions and lower minimum pressure. These animals also presented increased DBH levels at the Onuf´s nucleus, along with decreased c-Fos expression in the vlPAG. The present findings suggest that impairments in urinary function during hydrocephalus may be due to alterations in descending noradrenergic modulation. We propose that the effects of hydrocephalus in the decrease of vlPAG neuronal activation lead to a decrease in the control over the LC. The increased availability of noradrenaline production at the LC probably causes an exaggerated micturition reflex due to the increased innervation of the Onuf´s nucleus, accounting for the urinary impairments detected in hydrocephalic animals. The results of the study provide new insights into the neuronal underlying mechanisms of urinary dysfunction in hydrocephalus. Further research is needed to fully evaluate the translational perspectives of the current findings.

Side-effects of analgesic kyotorphin derivatives: advantages over clinical opioid drugs.

The adverse side-effects associated with opioid administration restrain their use as analgesic drugs and call for new solutions to treat pain. Two kyotorphin derivatives, kyotorphin-amide (KTP-NH2) and ibuprofen-KTP-NH2 (IbKTP-NH2) are promising alternatives to opioids: they trigger analgesia via an indirect opioid mechanism and are highly effective in several pain models following systemic delivery. In vivo side-effects of KTP-NH2 and IbKTP-NH2 are, however, unknown and were evaluated in the present study using male adult Wistar rats. For comparison purposes, morphine and tramadol, two clinically relevant opioids, were also studied. Results showed that KTP-derivatives do not cause constipation after systemic administration, in contrast to morphine. Also, no alterations were observed in blood pressure or in food and water intake, which were only affected by tramadol. A reduction in micturition was detected after KTP-NH2 or tramadol administrations. A moderate locomotion decline was detected after IbKTP-NH2-treatment. The side-effect profile of KTP-NH2 and IbKTP-NH2 support the existence of opioid-based mechanisms in their analgesic actions. The conjugation of a strong analgesic activity with the absence of the major side-effects associated to opioids highlights the potential of both KTP-NH2 and IbKTP-NH2 as advantageous alternatives over current opioids.

Outcomes of a QST Protocol in Healthy Subjects and Chronic Pain Patients: A Controlled Clinical Trial.

Chronic pain is an important cause of disability with a high burden to society. Quantitative sensory testing (QST) is a noninvasive multimodal method used to discriminate the function of nerve fibers. The aim of this study is to propose a new, reproducible, and less time-consuming thermal QST protocol to help characterize and monitor pain. Additionally, this study also compared QST outcomes between healthy and chronic pain subjects. Forty healthy young/adult medical students and fifty adult/elderly chronic pain patients were evaluated in individual sessions including pain history, followed by QST assessments divided into three proposed tests: pain threshold, suprathreshold, and tonic pain. In the chronic pain group, a significantly higher pain threshold (hypoesthesia) and a higher pain sensibility (hyperalgesia) were demonstrated at threshold temperature when compared to healthy participants. The sensitivity to the suprathreshold and tonic stimulus did not prove to be significantly different between both groups. The main results demonstrated that the heat threshold QST tests can be helpful in evaluating hypoesthesia and that the sensitivity threshold temperature test can demonstrate hyperalgesia in individuals with chronic pain. In conclusion, this study demonstrates the importance of using tools such as QST as a complement to detect changes in several pain dimensions.

Preclinical research in paclitaxel-induced neuropathic pain: a systematic review.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common consequence of cancer treatment and pain is a frequent complaint of the patients. Paclitaxel, a cytostatic drug, generates a well-described peripheral nerve injury and neuroinflammation, which may be experimentally mimicked in animal models. We conducted a systematic review analyzing the experimental design, reporting and mechanisms underlying paclitaxel-induced neuropathy in the included studies to establish the perspectives of translation of the current literature in models of CIPN. Methods: We elected studies published in Pubmed and Scopus between 1 January 2018 and 3 December 2022. Results: According to a defined mesh of keywords searched, and after applying exclusion and inclusion criteria, 70 original studies were included and analyzed in detail. Most studies used male Sprague-Dawley rats to induce paclitaxel-induced neuropathy, used low doses of paclitaxel, and the analyzed studies mainly focused at 14-28 days of CIPN. Mechanical nociceptive tests were preferred in the behavioral evaluation. The mechanisms under study were mainly neuroinflammation of peripheral nerves. The overall methodological quality was considered moderate, and the risk of bias was unclear. Discussion: Despite the ample preclinical research in paclitaxel-induced neuropathy, this systematic review alerts to some flaws in the experimental design along with limitations in reporting, e.g., lack of representation of both sexes in experimental work and the lack of reporting of the ARRIVE guidelines. This may limit the reproducibility of preclinical studies in CIPN. In addition, the clinical features of CIPN should be considered when designing animal experiments, such as sex and age of the CIPN patients. In this way the experimental studies aiming to establish the mechanisms of CIPN may allow the development of new drugs to treat CIPN and translation in the research of CIPN could be improved.

Neuroimaging uncovers neuronal and metabolic changes in pain modulatory brain areas in a rat model of chemotherapy-induced neuropathy - MEMRI and ex vivo spectroscopy studies.

Chemotherapy-induced neuropathy (CIN) is one of the most common complications of cancer treatment with sensory dysfunctions which frequently include pain. The mechanisms underlying pain during CIN are starting to be uncovered. Neuroimaging allows the identification of brain circuitry involved in pain processing and modulation and has recently been used to unravel the disruptions of that circuitry by neuropathic pain. The present study evaluates the effects of paclitaxel, a cytostatic drug frequently used in cancer treatment, at the neuronal function in the anterior cingulate cortex (ACC), hypothalamus and periaqueductal gray (PAG) using manganese-enhanced magnetic resonance imaging (MEMRI). We also studied the metabolic profile at the prefrontal cortex (PFC) and hypothalamus using ex vivo spectroscopy. Wistar male rats were intraperitoneal injected with paclitaxel or vehicle solution (DMSO). The evaluation of mechanical sensitivity using von Frey test at baseline (BL), 21 (T21), 28 (T28), 49 (T49) and 56 days (T56) after CIN induction showed that paclitaxel-injected rats presented mechanical hypersensitivity from T21 until T56 after CIN induction. The evaluation of the locomotor activity and exploratory behaviors using open-field test at T28 and T56 after the first injection of paclitaxel revealed that paclitaxel-injected rats walked higher distance with higher velocity at late point of CIN accompanied with a sustained exhibition of anxiety-like behaviors. Imaging studies performed using MEMRI at T28 and T56 showed that paclitaxel treatment increased the neuronal activation in the hypothalamus and PAG at T56 in comparison with the control group. The analysis of data from ex vivo spectroscopy demonstrated that at T28 paclitaxel-injected rats presented an increase of N-acetyl aspartate (NAA) levels in the PFC and an increase of NAA and decrease of lactate (Lac) concentration in the hypothalamus compared to the control group. Furthermore, at T56 the paclitaxel-injected rats presented lower NAA and higher taurine (Tau) levels in the PFC. Together, MEMRI and metabolomic data indicate that CIN is associated with neuroplastic changes in brain areas involved in pain modulation and suggests that other events involving glial cells may be happening.

Research in Mindfulness Interventions for Patients With Fibromyalgia: A Critical Review.

Fibromyalgia is one of the most common causes of widespread chronic pain. It has a huge impact on the quality of life, namely because it appears earlier in life than most of the chronic pain conditions. Furthermore, emotional-cognitive distress factors, such as depression and anxiety, are a common feature in patients with fibromyalgia. The neurobiological mechanisms underlying fibromyalgia remain mostly unknown. Among non-pharmacological treatments, cognitive-behavioral therapy has been used during the last decade, namely with the enrolment of patients in programs of mindfulness-based stress reduction (MBSR) and in mindfulness-based interventions (MBI). We critically analyzed the literature to search for scientific evidence for the use of MBI in fibromyalgia. The studies were evaluated as to several outcomes of fibromyalgia improvement along with aspects of the study design which are currently considered relevant for research in mindfulness. We conclude that despite the sparsity of well-structured longitudinal studies, there are some promising results showing that the MBI are effective in reducing the negative aspects of the disease. Future design of studies using MBI in fibromyalgia management should be critically discussed. The importance of active controls, evaluation of sustained effects along with investigation of the subserving neurobiological mechanisms and detailed reports of possible adverse effects should be considered.