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Emerging evidence suggests a detrimental impact of COVID-19 illness on the continued hippocampal neurogenesis in adults. In contrast, the existing literature supports an enhancing effect of COVID-19 vaccination on adult hippocampal neurogenesis. Vaccines against respiratory infections, including influenza, have been shown to enhance hippocampal neurogenesis in adult-age animals. We propose that a similar benefit may happen in COVID-19 vaccinated adults. The vaccine-induced enhancement of the hippocampal neurogenesis in adults thus may protect against age-related cognitive decline and mental disorders. It alsohints at an added mental health benefit of the COVID-19 vaccination programs in adults.

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MOR(CA)) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3–4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished on chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HT(3)R antagonist ondansetron; the 5-HT(2A)R antagonist MDL-11 939 had no effect. Second, to test for MOR(CA), we microinjected the MOR inverse agonist d-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and/or neutral opioid receptor antagonist 6β-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws; 6β-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MOR(CA), rather than an opioid ligand-dependent mechanism, maintains LS in remission. We conclude that incision establishes LS in descending RVM 5-HT neurons that drives pronociceptive 5-HT(3)R signaling in the dorsal horn, and this LS is tonically opposed by MOR(CA) in the RVM. The 5-HT(3) receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain. SIGNIFICANCE STATEMENT Surgery leads to latent pain sensitization and a compensatory state of endogenous pain control that is maintained long after tissue healing. Here, we show that either chemogenetic inhibition of serotonergic neuron activity in the RVM or pharmacological inhibition of 5-HT(3) receptor signaling at the spinal cord blocks behavioral signs of postsurgical latent sensitization. We conclude that MOR(CA) in the RVM opposes descending serotonergic facilitation of LS and that the 5-HT(3) receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.

Ha transcurrido más de un año y medio desde el inicio de la pandemia debida a la enfermedad por coronavirus 2019 (COVID-19), y el mundo se esfuerza por contenerla. Al ser causada por un virus hasta ahora desconocido, en el periodo inicial hubo una escasez extrema de conocimientos sobre los mecanismos de la enfermedad, lo que dificultó las medidas preventivas y terapéuticas contra el COVID-19. En un esfuerzo por comprender sus mecanismos patogénicos, se han llevado a cabo extensos estudios experimentales en todo el mundo con experimentos basados en cultivos celulares, organoides de tejidos humanos y modelos animales, enfocados en varios aspectos de la enfermedad, como las propiedades del virus, su tropismo tisular y su patogénesis específica en ciertos órganos, la implicación de los sistemas fisiológicos y la respuesta inmunitaria humana contra la infección. El enorme conocimiento científico acumulado sobre todos los aspectos del COVID-19 cambió el escenario, de una gran desolación, a la esperanza. A pesar de que se han producido avances espectaculares en todos estos aspectos, quedan múltiples lagunas de conocimiento que deben abordarse en futuros estudios. Además, desde el inicio de la primera oleada de COVID-19 han surgido en todo el mundo múltiples variantes del coronavirus tipo 2 del síndrome respiratorio agudo severo (SARS-CoV-2), que parecen tener mayor transmisibilidad/virulencia y capacidad de escape inmunológico que la cepa de tipo salvaje. En esta revisión narramos los avances realizados desde el inicio de la pandemia en nuestros conocimientos sobre los mecanismos del COVID-19 en el cuerpo humano, incluyendo las interacciones virus-huésped, las manifestaciones pulmonares y sistémicas, las desregulaciones inmunológicas, las complicaciones, la vulnerabilidad específica del huésped y las consecuencias a largo plazo en los supervivientes. Además, ofrecemos una breve revisión de las pruebas actuales que explican los mecanismos moleculares que confieren mayor transmisibilidad, virulencia y capacidad de escape inmunológico a las variantes emergentes del SARS-CoV-2.

Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor in the host-cells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entry-receptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine-acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.

BACKGROUND A newly emerged SARS-CoV-2 variant B.1.1.529 worried the health policy makers worldwide due to a large number of mutations in its genomic sequence, especially in the spike protein region. World Health Organization (WHO) designated it as a global variant of concern (VOC) and was named 'Omicron.' Following Omicron's emergence, a surge in new COVID-19 cases was reported globally, primarily in South Africa (SA). OBJECTIVE We aimed to understand whether the Omicron had an epidemiological advantage over existing variants. METHODS We performed an in silico analysis of the complete genomic sequences of Omicron available on GISAID to analyze the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. In addition, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period of 01 Oct-29 Nov 2021) with the matched epidemiological data (new COVID-19 cases and deaths) from SA. RESULTS Compared to the current list of global VOCs/VOIs (as per WHO), Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with the Alpha variant for the complete sequence and RBM. The mutations were found primarily condensed in the spike region (28-48) of the virus. Further, the mutational analysis showed enrichment for the mutations decreasing ACE2-binding affinity and RBD protein expression, in contrast, increasing the propensity of immune escape. An inverse correlation of Omicron with Delta variant was noted (r=-0.99, p< .001, 95% CI: -0.99 to -0.97) in the sequences reported from SA post-emergence of the new variant, later showing a decrease. There was a steep rise in the new COVID-19 cases in parallel with the increase in the proportion of Omicron since the first case (74-100%). In contrary, the incidences of new deaths was not increased (r=-0.04, p>0.05, 95% CI =-0.52 to 0.58). CONCLUSIONS In silico analysis of the viral genomic sequences suggest that the Omicron variant has more remarkable immune escape ability than the existing VOCs/VOIs, including Delta, but lesser virulence/lethality than other reported variants. The higher power for immune escape for Omicron was a likely reason for the surge in COVID-19 cases and soon becoming a globally dominant strain. They were more infectious but less lethal than the existing variants, hence outpaced them, thus scripting the pandemic's downfall.

Tissue injury creates a delicate balance between latent pain sensitization (LS) and compensatory endogenous analgesia. Inhibitory G protein-coupled receptor (GPCR) interactions that oppose LS, including μ-opioid receptor (MOR) and neuropeptide Y Y1 receptor (Y1R) activity, persist in the spinal cord dorsal horn (DH) for months, even after the resolution of normal pain thresholds. Here, we demonstrate that following recovery from surgical incision, a potent endogenous analgesic synergy between MOR and Y1R activity persists within DH interneurons to reduce the intensity and duration of latent postoperative hyperalgesia and ongoing pain. Failure of such endogenous GPCR signaling to maintain LS in remission may underlie the transition from acute to chronic pain states.

Manifestation of neurological symptoms in certain patients of coronavirus disease-2019 (COVID-19) has warranted for their virus-induced etiogenesis. SARS-CoV-2, the causative agent of COVID-19, belongs to the genus of betacoronaviruses which also includes SARS-CoV-1 and MERS-CoV; causative agents for severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, respectively. Studies demonstrating the neural invasion of SARS-CoV-2 in vivo are still scarce, although such characteristics of certain other betacoronaviruses are well demonstrated in the literature. Based on the recent evidence for the presence of SARS-CoV-2 host cell entry receptors in specific components of the human nervous and vascular tissue, a neural (olfactory and/or vagal), and a hematogenous-crossing the blood-brain barrier, routes have been proposed. The neurological symptoms in COVID-19 may also arise as a consequence of the "cytokine storm" (characteristically present in severe disease) induced neuroinflammation, or co-morbidities. There is also a possibility that, there may be multiple routes of SARS-CoV-2 entry into the brain, or multiple mechanisms can be involved in the pathogenesis of the neurological symptoms. In this review article, we have discussed the possible routes of SARS-CoV-2 brain entry based on the emerging evidence for this virus, and that available for other betacoronaviruses in literature.

Tissue injury induces a long-lasting latent sensitization of spinal nociceptive signaling that is kept in remission by an opposing μ-opioid receptor constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited three weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or β-funaltrexamine subcutaneously and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of latent sensitization and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In latent sensitization animals tested three weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One-third of Fos+ profiles co-expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co-expressed tdTomato+ in Oprm1(Cre)::tdTomato transgenic mice. CeA microinjection of naltrexone (1 μg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra-CeA injection of the MOR-selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that mu-opioid receptors in the capsular subdivision of the right central nucleus of the amygdala prevent the transition from acute to chronic postoperative pain.

Background Emergence of the new SARS-CoV-2 variant B.1.1.529 worried health policy makers worldwide due to a large number of mutations in its genomic sequence, especially in the spike protein region. The World Health Organization (WHO) designated this variant as a global variant of concern (VOC), which was named “Omicron.” Following Omicron’s emergence, a surge of new COVID-19 cases was reported globally, primarily in South Africa. Objective The aim of this study was to understand whether Omicron had an epidemiological advantage over existing variants. Methods We performed an in silico analysis of the complete genomic sequences of Omicron available on the Global Initiative on Sharing Avian Influenza Data (GISAID) database to analyze the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. In addition, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period from October 1 to November 29, 2021) with matched epidemiological data (new COVID-19 cases and deaths) from South Africa. Results Compared with the current list of global VOCs/variants of interest (VOIs), as per the WHO, Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with the Alpha variant for the complete sequence and the RBM. The mutations were found to be primarily condensed in the spike region (n=28-48) of the virus. Further mutational analysis showed enrichment for the mutations decreasing binding affinity to angiotensin-converting enzyme 2 receptor and receptor-binding domain protein expression, and for increasing the propensity of immune escape. An inverse correlation of Omicron with the Delta variant was noted (r=–0.99, P.05; 95% CI –0.52 to 0.58). Conclusions In silico analysis of viral genomic sequences suggests that the Omicron variant has more remarkable immune-escape ability than existing VOCs/VOIs, including Delta, but reduced virulence/lethality than other reported variants. The higher power for immune escape for Omicron was a likely reason for the resurgence in COVID-19 cases and its rapid rise as the globally dominant strain. Being more infectious but less lethal than the existing variants, Omicron could have plausibly led to widespread unnoticed new, repeated, and vaccine breakthrough infections, raising the population-level immunity barrier against the emergence of new lethal variants. The Omicron variant could have thus paved the way for the end of the pandemic.

BackgroundA newly emerged SARS-CoV-2 variant B.1.1.529 has worried the health policy makers worldwide due to the presence of a large number of mutations in its genomic sequence, especially in the spike protein region. World Health Organization (WHO) has designated it as a global variant of concern (VOC) and has named as ‘Omicron’. A surge in new COVID-19 cases have been reported from certain geographical locations, primarily in South Africa (SA) following the emergence of Omicron.Materials and methodsWe performed an in silico analysis of the complete genomic sequences of Omicron available on GISAID (until 2021-12-10) to predict the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. The mutations present at the receptor binding domain (RBD) of the variants were assessed using an open analysis pipeline which integrates a yeast-display platform with deep mutational scanning. Further, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period of 01 Oct-10th Dec, 2021) with the current epidemiological data (new COVID-19 cases and deaths) from SA to understand whether the Omicron has an epidemiological advantage over existing variants.ResultsCompared to the current list of global VOCs/VOIs (as per WHO) Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with Alpha variant for the complete sequence as well as for RBM. The mutations were found primarily condensed in spike region (28-48) of the virus. Further, the mutational analysis showed enrichment for the mutations decreasing ACE2-binding affinity and RBD protein expression, in contrast, increasing the propensity of immune escape. An inverse correlation of Omicron with Delta variant was noted (r=-0.99, p< .001, 95% CI: -0.99 to - 0.97) in the sequences reported from SA post-emergence of the new variant, later showing a decrease. There has been a steep rise in the new COVID-19 cases in parallel with increase in the proportion of Omicron since the first case (74-100%), on the contrary, the incidences of new deaths have not been increased (r=-0.04, p>0.05, 95% CI =-0.52 to 0.58).ConclusionsOmicron may have greater immune escape ability than the existing VOCs/VOIs. However, there are no clear indications coming out from the predictive mutational analysis that the Omicron may have higher virulence/lethality than other variants, including Delta. The higher ability for immune escape may be a likely reason for the recent surge in Omicron cases in SA.HighlightsHigher immune escape ability than the existing VOCs/VOIsNo clear indications of increased affinity for ACE2 bindingDriving a new COVID-19 wave in South AfricaOutcompeting Delta variantCurrently, no clear evidence for increased virulence/lethality

Latent sensitization (LS) of pain engages pronociceptive signaling pathways in the dorsal horn that include NMDA receptor (NMDAR)→adenylyl cyclase-1 (AC1)→protein kinase A (PKA), and exchange proteins directly activated by cyclic AMP (Epacs). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal κ opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302, which reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but not astrocytes (GFAPs) nor microglia (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission. In both sexes, intrathecal MK-801 (an NMDAR competitive antagonist) prevented LY2456302-evoked reinstatement of hyperalgesia as did AC1 gene deletion or the AC1 inhibitor NB001. NB001 also prevented stimulus-evoked pERK. In both sexes, the Epac inhibitor ESI-09 prevented reinstatement, whereas the Epac activator 8-CPT reinstated hyperalgesia. By contrast, the PKA inhibitor H89 prevented reinstatement only in male mice, whereas the PKA activator 6-bnz-cAMP itself evoked reinstatement at all doses tested (3–30 nmol, i.t.). In neither sex did incision change gene expression of KOR, GluN1, PKA, or Epac1 in dorsal horn. We conclude that sustained KOR signaling inhibits spinal PKA-dependent mechanisms that drive postoperative LS in a sex-dependent manner. Our findings support the development of AC1, PKA, and Epac inhibitors toward a new pharmacotherapy for chronic postoperative pain.SIGNIFICANCE STATEMENTBecause of neural mechanisms that are not well understood, men and women respond differently to treatments for chronic pain. We report that surgical incision recruits a pronociceptive latent pain sensitization that persisted for over a year and was kept in check by the sustained analgesic activity of κ opioid receptors. NMDAR→AC1→cAMP→Epac signaling pathways in the dorsal horn of the spinal cord maintain latent sensitization in both males and females; however, only males recruit a PKA-dependent mechanism. This work presents a novel male-specific mechanism for the promotion of chronic postoperative pain.

Recent epidemiological studies analysing sex-disaggregated patient data of coronavirus disease 2019 (COVID-19) across the world revealed a distinct sex bias in the disease morbidity as well as the mortality – both being higher for the men. Similar antecedents have been known for the previous viral infections, including from coronaviruses, such as severe acute respiratory syndrome (SARS) and middle-east respiratory syndrome (MERS). A sound understanding of molecular mechanisms leading to the biological sex bias in the survival outcomes of the patients in relation to COVID-19 will act as an essential requisite for developing a sex-differentiated approach for therapeutic management of this disease. Recent studies which have explored molecular mechanism(s) behind sex-based differences in COVID-19 pathogenesis are scarce; however, existing evidence, for other respiratory viral infections, viz. SARS, MERS and influenza, provides important clues in this regard. In attempt to consolidate the available knowledge on this issue, we conducted a systematic review of the existing empirical knowledge and recent experimental studies following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The qualitative analysis of the collected data unravelled multiple molecular mechanisms, such as evolutionary and genetic/epigenetic factors, sex-linkage of viral host cell entry receptor and immune response genes, sex hormone and gut microbiome-mediated immune-modulation, as the possible key reasons for the sex-based differences in patient outcomes in COVID-19.

Introduction: Intense immunological dysregulation including immune cell lesions have been characteristically observed in severe cases of Coronavirus Disease-2019 (COVID-19), for which molecular mechanisms are least understood. A study of physiological expressions of SARS-CoV-2 host cell entry related factors in immune system components may help explain molecular mechanisms involved in COVID-19 immunopathology. Materials and Methods: Transcriptomic and proteomic expression metadata for SARS-CoV-2 host cell entry receptor ACE2 and entry associated proteases (TMPRSS2, CTSL, and FURIN) were analysed in silico across immune system components including blood lineage cells. Results: ACE2 was not-detected in any of the studied immune cell components, however, varying transcriptomic and proteomic expressions were observed, for TMPRSS2, CTSL, and FURIN. Conclusions: Non-detectable expressions of SARS-CoV-2 host cell entry receptor ACE2 in immune system components or blood lineage cells indicate it doesn’t mediate immune cell lesions in COVID-19. Alternative mechanisms need to be explored for COVID-19 immuno-pathogenesis.

Infiltration of surgical wound with local anaesthetics attenuate postoperative pain. However, side effects can also occur. Somatostatin (SST) and its analogues like octreotide reportedly reduce peripheral sensitisation. The current study evaluates peripherally mediated antinociceptive effect of SST in a rat model of postoperative pain. This was compared with bupivacaine and morphine under identical experimental conditions.Randomised vehicle-controlled blind study.Pain research laboratory, All India Institute of Medical Sciences, New Delhi from February 2014 to July 2017.Rodent hind paw incision model.Sprague-Dawley rats were subjected to incision and one of the following drugs administered into the open wound once by a micropipette: SST (10, 30 or 100 μg), bupivacaine (3, 10, 30, 50 or 100 μg) or morphine (100 μg). Antinociceptive effect of SST was further evaluated for its reversibility, site of action, effect on spinal c-fos expression and blood glucose level. The site of action of morphine was also investigated.Nociception was estimated by nonevoked (guarding behaviour) and evoked (mechanical allodynia and thermal hyperalgesia) pain behaviours between 2 h and days 4 to 7.Nociception was maximum 2 h after incision. SST (10 to 100 μg) significantly attenuated guarding behaviour between 2 h and day 2. A delayed inhibitory effect was observed on allodynia. Bupivacaine (10 to 100 μg doses) similarly decreased guarding score up to day 2 though evoked pain behaviours were relatively unaffected. In contrast, morphine produced a potent but transient inhibitory effect on guarding score at 2 h, which was mediated by both peripheral and central opioid receptors. The antinociceptive effect of SST was peripherally mediated by type 2 receptors and was associated with decreased c-fos staining. Blood glucose level was unaltered.Guarding behaviour, which likely represents pain-at-rest following surgery, was attenuated by both bupivacaine and SST to comparable extents. This novel peripherally mediated antinociceptive effect of SST needs further evaluation.

Neuroanatomical and behavioral evidence indicates that neuropeptide Y Y1 receptor-expressing interneurons (Y1-INs) in the superficial dorsal horn (SDH) are predominantly excitatory and contribute to chronic pain. Using an adult ex vivo spinal cord slice preparation from Y1eGFP reporter mice, we characterized firing patterns in response to steady state depolarizing current injection of GFP-positive cells in lamina II, the great majority of which expressed Y1 mRNA (88%). Randomly sampled and Y1eGFP neurons exhibited five firing patterns: tonic (TF), initial burst (IBF), phasic (PF), delayed short-latency 180 ms (DLLF). When studied at resting membrane potential, most RS neurons exhibited delayed firing, while most Y1eGFP neurons exhibited phasic firing and not delayed firing. A preconditioning membrane hyperpolarization produced only subtle changes in the firing patterns of randomly sampled neurons, but dramatically shifted Y1eGFP neurons to DSLF (46%) and DLLF (24%). In contrast to randomly sampled DSLF neurons which rarely exhibited spike frequency adaptation, Y1eGFP DSLF neurons were almost always rapidly adapting, a characteristic of nociceptive-responsive SDH neurons. Rebound spiking was more prevalent in Y1eGFP neurons (6% RS vs 32% Y1eGFP), indicating enrichment of T-type calcium currents. Y1eGFP DSLF neurons exhibited fast A-type potassium currents that are known to delay or limit action potential firing, and these were of smaller current density as compared to randomly sampled DSLF neurons. Our results inspire future studies to determine whether tissue or nerve injury downregulates channels that contribute to A-currents, thus potentially unmasking T-type calcium channel activity and membrane hyperexcitability in Y1-INs, leading to persistent pain.KEYPOINTSNeuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain.For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice.Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF).Y1eGFP DSLF neurons were almost always rapidly adapting and often exhibited rebound spiking, characteristics of spinal pain neurons under the control of T-type calcium channels.These results inspire future studies to determine whether tissue or nerve injury downregulates the channels that underlie A-currents, thus unmasking membrane hyperexcitability in Y1- expressing dorsal horn neurons, leading to persistent pain

The pandemic of the coronavirus disease, 2019 (COVID-19) has caused millions to suffer from the disease and to die globally. Global epidemiological statistics reflect, significantly more numbers of men, aged, those suffering from co-morbidities, and people facing socio-economic inequalities, such as, racial/ethnic minorities, have been affected by COVID-19. Why the disease affects more to these specific population groups is intriguing the researchers globally. Emerging literature in COVID-19 indicates crucial role of factors intrinsic to the host behind such poor outcomes in selected individuals. Our comprehensive review of existing literature unravels a range of host factors which could have decisive role in patient outcomes in COVID-19, in terms of contracting infections, disease severity, and mortality, such as: age, sex, co-morbidities, genetic and phenotypic factors (e.g. polymorphisms or mutations, blood group etc.), clinical and laboratory parameters (at the time of hospital admission), cross protection from previous respiratory virus infections and childhood vaccinations, gut-microbiome, life style, habits and behavior (smoking and substance abuse), and socio-economic and systemic inequalities. In this article, we discuss in brief the most definitive and updated evidence for each of these host factors.

Neuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain. For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice. Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF). Y1eGFP DSLF neurons were almost always rapidly adapting and often exhibited rebound spiking, characteristics of spinal pain neurons under the control of T-type calcium channels. These results will inspire future studies to determine whether tissue or nerve injury downregulates the channels that underlie A-currents, thus unmasking membrane hyperexcitability in Y1-expressing dorsal horn neurons, leading to persistent pain.Neuroanatomical and behavioural evidence indicates that neuropeptide Y Y1 receptor-expressing interneurons (Y1-INs) in the superficial dorsal horn (SDH) are predominantly excitatory and contribute to chronic pain. Using an adult ex vivo spinal cord slice preparation from Y1eGFP reporter mice, we characterized firing patterns in response to steady state depolarizing current injection of GFP-positive cells in lamina II, the great majority of which expressed Y1 mRNA (88%). Randomly sampled (RS) and Y1eGFP neurons exhibited five firing patterns: tonic, initial burst, phasic, delayed short-latency180 ms (DSLF) and delayed long-latency180 ms (DLLF). When studied at resting membrane potential, most RS neurons exhibited delayed firing, while most Y1eGFP neurons exhibited phasic firing. A preconditioning membrane hyperpolarization produced only subtle changes in the firing patterns of RS neurons, but dramatically shifted Y1eGFP neurons to DSLF (46%) and DLLF (24%). In contrast to RS DSLF neurons, which rarely exhibited spike frequency adaptation, Y1eGFP DSLF neurons were almost always rapidly adapting, a characteristic of nociceptive-responsive SDH neurons. Rebound spiking was more prevalent in Y1eGFP neurons (6% RS vs. 32% Y1eGFP), indicating enrichment of T-type calcium currents. Y1eGFP DSLF neurons exhibited fast A-type potassium currents that are known to delay or limit action potential firing and exhibited smaller current density as compared to RS DSLF neurons. Our results will inspire future studies to determine whether tissue or nerve injury downregulates channels that contribute to A-currents, thus potentially unmasking T-type calcium channel activity and membrane hyperexcitability in Y1-INs, leading to persistent pain.

Lack of standardised therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.

Graphical abstract, COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Based on the human tissue specific distribution of SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 and other supportive evidence from the literature, we hypothesize that SARS-CoV-2 host cell entry receptor—ACE2 based mechanism in GI tissue may be involved in COVID-19 (i) in the pathogenesis of digestive symptoms, (ii) in increased diabetic complications, (iii) in disease recurrence.

The paucity of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific virulence factors has greatly hampered the therapeutic management of patients with coronavirus disease 2019 (COVID-19). Recently, a cluster of studies appeared, which presented empirical evidence for SARS-CoV-2-specific virulence factors that can explain key elements of COVID-19 pathology. These studies unravel multiple structural and nonstructural specifics of SARS-CoV-2, such as a unique FURIN cleavage site, papain-like protease (SCoV2-PLpro), ORF3b and nonstructural proteins, and dynamic conformational changes in the structure of spike protein during host cell fusion, which give it an edge in infectivity and virulence over previous coronaviruses causing pandemics. Investigators provided robust evidence that SARS-CoV-2-specific virulence factors may have an impact on viral infectivity and transmissibility and disease severity as well as the development of immunity against the infection, including response to the vaccines. In this article, we are presenting a summarized account of the newly reported studies.

Recent epidemiological studies analysing sex disaggregated patient data in COVID-19 across the world revealed a distinct sex bias in the disease morbidity as well as the mortality— both being higher for the men. Similar antecedents have been known for the previous viral infections, including from coronaviruses, such as severe acute respiratory syndrome (SARS) and middle-east respiratory syndrome (MERS). A sound understanding of the molecular mechanisms leading the biological sex bias in the survival outcomes of the patients in relation to COVID-19 will act as an essential requisite for developing a sex differentiated approach for therapeutic management of this disease. Recent studies which have explored molecular mechanism(s) behind sex-based differences in COVID-19 pathogenesis are scarce, however, existing evidence, for other viral infections, provides important clues in this regard. In attempt to consolidate the available knowledge on this issue, we performed a systematic review of the existing empirical knowledge and recent experimental studies following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The online literature sources including PubMed, Medline (EBSCO & Ovid), Google Scholar, Science Direct, Scopus, Bio Medical and Web of Science (WoS) were searched for the relevant data. Additionally, published literatures were also explored extensively. The time period taken to review the COVID-19 specific data was from December 1, 2019 to November 20, 2020. The qualitative analysis of the collected data unravelled multiple molecular mechanisms, such as sex-linkage of viral host cell entry receptor and immune genes, sex hormone and gut microbiome mediated immune-modulation, as the possible reasons for the sex-based differences in patient outcomes in COVID-19.

Introduction The superficial laminae of the spinal cord are crucial sites for the transmission of incoming noxious information. Calcitonin gene-related peptide (CGRP) is released from the presynaptic nerve terminals in these laminae. One of the objectives was to evaluate the temporospatial pattern of expression of CGRP following paw incision in rats. Paw incision-induced nociception mimics postoperative pain in humans. The next objective was to administer a specific CGRP receptor antagonist directly into the intrathecal space and observe the antinociceptive effect, which was then compared to morphine. Material and methods Sprague Dawley rats were subjected to incision on the right hind paw. The related spinal cord segments (L4-5) were isolated at different time intervals after incision and immunostained for CGRP. A different set of rats were implanted with intrathecal catheter and administered saline (control) or BIBN 4096 (CGRP antagonist) or morphine (10 μg/10 μl) and then subjected to paw incision. Nociception was evaluated at different time intervals up to day 7. Results Expression of CGRP was observed over laminae I and outer part of lamina II. Synaptic terminals could be discerned containing CGRP. Following incision, the expression decreased abruptly at 2 h. However, at 12 h, the expression had increased. Between days 1–5, the expression decreased again towards basal levels. The antinociceptive effect of BIBN was comparatively less than morphine, which robustly inhibited all three pain parameters at 2 h after incision. Discussion Immunohistochemistry revealed that CGRP was involved in the transmission of nociception. However, blocking its action did not produce a robust antinociceptive effect.

Nerve growth factors (NGFs), especially the prototype NGF and brain-derived neurotrophic factor (BDNF), have a diverse array of functions in the central nervous system through their peculiar set of receptors and intricate signaling. They are implicated not only in the development of the nervous system but also in regulation of neurocognitive functions like learning, memory, synaptic transmission, and plasticity. Evidence even suggests their role in continued neurogenesis and experience-dependent neural network remodeling in adult brain. They have also been associated extensively with brain disorders characterized by neurocognitive dysfunction. In the present article, we aimed to make an exhaustive review of literature to get a comprehensive view on the role of NGFs in neurocognitive functions in health and disease. Starting with historical perspective, distribution in adult brain, implied molecular mechanisms, and developmental basis, this article further provides a detailed account of NGFs’ role in specified neurocognitive functions. Furthermore, it discusses plausible NGF-based homeostatic and adaptation mechanisms operating in the pathogenesis of neurocognitive disorders and has presents a survey of such disorders. Finally, it elaborates on current evidence and future possibilities in therapeutic applications of NGFs with an emphasis on recent research updates in drug delivery mechanisms. Conclusive remarks of the article make a strong case for plausible role of NGFs in comprehensive regulation of the neurocognitive functions and pathogenesis of related disorders and advocate that future research should be directed to explore use of NGF-based mechanisms in the prevention of implicated diseases as well as to target these molecules pharmacologically.

Noxious stimuli activate small to medium-sized dorsal root ganglion (DRG) neurons. Intense noxious stimuli result in the release of substance P (SP) from the central terminals of these neurons. It binds to the neurokinin type 1 receptor (NK1r) and sensitises the dorsal horn neurons. SP is also released from the peripheral terminals leading to neurogenic inflammation. However, their individual contribution at spinal and peripheral levels to postincisional nociception has not been delineated as yet.Sprague-Dawley rats were administered different doses (3-100 μg) of an NK1r antagonist (L760735) by intrathecal (i.t.) route before hind paw incision. On the basis of its antinociceptive effect on guarding behaviour, the 30 μg dose was selected for further study. In different sets of animals, this was administered i.t. (postemptive) and intrawound (i.w.). Finally, in another group, drug (30 μg) was administered through both i.t and i.w. routes. The antinociceptive effect was assessed and compared. Expression of SP was examined in the spinal cord. Intrawound concentration of SP and inflammatory mediators was also evaluated.Postemptive i.t. administration significantly attenuated guarding and allodynia. Guarding was alone decreased after i.w. drug treatment. Combined drug administration further attenuated all nociceptive parameters, more so after postemptive treatment. Expression of SP in the spinal cord decreased post incision but increased in the paw tissue. Inflammatory mediators like the nerve growth factor also increased after incision.In conclusion, SP acting through the NK1r appears to be an important mediator of nociception, more so at the spinal level. These findings could have clinical relevance.

Apart from their established role in embryonic development, neurotrophins (NTs) have diverse functions in the nervous system. Their role in the integration of physiological and biochemical aspects of the nervous system is currently attracting much attention. Based on a systematic analysis of the literature, we here propose a new paradigm that, by exploiting a novel role of NTs, may help explain the genesis of stress-related psychiatric disorders, opening new avenues for better management of the same. We hypothesize that NTs as an integrated network play a crucial role in maintaining an indivdual's psychological wellbeing. Given the evidence that stress can induce chronic disruption of the hypothalamic-pituitary-adrenal (HPA) axis which, in turn, is causally linked to several psychiatric disorders, this function may be mediated through the homeostatic mechanisms governing regulation of this axis. In fact, NTs, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are known to participate in neuroendocrine regulation. Recent studies suggest epigenetic modification of NT-HPA axis interplay in the precipitation of psychiatric disorders. Our article highlights why this new knowledge regarding NTs should be considered in the etiogenesis and treatment of stress-induced psychopathology.

Apart from their established role in embryonic development Nerve Growth Factors (NGFs) have diverse functions in the nervous system. Their role in integration of physiological functioning ofthe nervous systemis now attracting attention. In the present analysis, we propose anovel paradigmabout a novel role of NGFs: NGFs play imperative role in maintaining psychological integrity of an individual as a biological system. This function may be mediated through HPA-axis- operated homeostatic mechanisms; stress induced disruption of which may lead to psychiatric disorders. Current literature suggests existence of constitutive homeostatic regulatory mechanismsfor NGFs disruption which may lead to pertinent and imperativebehavioural effects. NGFsare known to play crucial role in endocrine regulation. This is especially true with the prototype ‘NGF’ and Brain Derived Neurotrophic Factor (BDNF). These moieties have been observed to play important function in maintaining neuro-endocrine homeostasis thereby having a profound impact on the psychological health of an individual. Role of NGFs and HPA-axis activation (in separate studies) in developing psychiatric disorders - especially those born of stress - have been reported. Literature suggests their unique interplay for producing a common effect which might be implicated in stress induced genesis of psychiatric disorders. This aspect, therefore, needs to be elucidated further as a disease etiogenesis model. This model may yield important insights intothe biology ofpsychiatric disorders and may open ways for new therapeutic approaches.

Apart from their established role in embryonic development Nerve Growth Factors (NGFs) have diverse functions in the nervous system. Their role in integration of physiological functioning of the nervous system is now attracting attention. In the present analysis, we propose a new paradigm about a novel role of NGFs. We hypothesize that NGFs play imperative role in maintaining psychological integrity of an individual as a biological system. This function may be mediated through HPA-axis- operated homeostatic mechanisms; stress induced disruption of which may lead to psychiatric disorders. Current literature suggests existence of constitutive homeostatic regulatory mechanisms for NGFs disruption which may lead to important behavioural effects. NGFs have been shown to play crucial parts in endocrine regulation. This is especially true with the prototype ‘NGF’ and Brain Derived Neurotrophic Factor (BDNF). These moieties have been observed to play important role in maintaining neuro-endocrine homeostasis thereby having a profound impact on the psychological health of an individual. Role of NGFs and HPA-axis activation (in separate studies) in developing psychiatric disorders - especially those born of stress - have been established. Literature suggests their unique interplay for producing a common effect which might be implicated in stress induced genesis of psychiatric disorders. This aspect, therefore, needs to be elucidated further as a disease etiogenesis model. This model may yield important insights into the evolution of psychiatric disorders and may open ways for new therapeutic approaches.

Wounds associated with injuries such as burns can produce moderate to severe pain. Besides causing distress to the patient, unrelieved pain could delay healing owing to stress-related problems. Thus, pain needs to be treated as early as possible after injury. It was hypothesised that local treatment of wounds with appropriate analgesic drugs could attenuate pain. HOE 140, a bradykinin receptor antagonist, reduced acute inflammatory pain in rats after intrawound administration. In this study, the analgesic effect of dimethylsulphoxide (DMSO) was investigated in a similar hind-paw incision model in rats. An extremely small quantity (10 µl) of 100% DMSO was administered into the incision site just before closure of the wound. It persistently attenuated guarding behaviour in rats over a period of 3 days without affecting thermal hyperalgesia or allodynia. Accumulated evidence indicates that guarding is equivalent to pain at rest in humans. The possible mechanisms of the analgesic effect could be inhibition of C group of peripheral nerve fibres or even free radical scavenging. Healing of the wound was found to be normal at the end of the study period. In conclusion, DMSO could be useful in the treatment of acute pain resulting from tissue injuries such as burns.

Background:Sciatic nerve ligation causes neuropathic pain with chronic constriction injury (CCI). However, there is no published report on the effect of pioglitazone as an antidepressant in the treatment of depression induced by neuropathic pain with CCI in rats. The aim of this study was to evaluate the effect of pioglitazone as an antidepressant by targeting oxidative stress by the peripheral neuropathic pain model using the CCI of the sciatic nerve.Methods:Behavioral studies were carried out to measure thermal hyperalgesia and cold allodynia as markers of neuropathic pain and force swim test for depression. These were followed by estimation of biochemical parameters which include lipid peroxidation (LPO), reduced glutathione, catalase, nitrite and superoxide dismutase (SOD) in the rat brains as a measure of oxidative stress. We administered two intraperitoneal doses of pioglitazone (4.5 and 9.0 mg/kg, i.p.) to the treated group for 28 consecutive days from the day of injury and behavioral as well as biochemical evaluations were performed.Results:The results suggested that the administration of pioglitazone significantly countered the neuropathic pain induced depression as interpreted through elevated pain threshold of tactile allodynia and thermal hyperalgesia followed by decreased immobility time in the 9.0 mg/kg dose group.Conclusions:It may be concluded that the oxidative stress plays a critical role in the pathogenesis of neuropathic pain and depression as evidenced by the behavioral studies and the changes in the levels of lipid peroxidase, nitrite, catalase, and glutathione and SOD.

Acute tissue damage is accompanied by synthesis of nitric oxide (NO) in the inflamed tissue as well as in the spinal cord. NO release at the spinal level is likely involved in the neuroplastic changes contributing to pain. Also, previous studies indicate that this could be due to the inducible isoform of the nitric oxide synthase (iNOS) enzyme. Though, the role of NO has been investigated in several animal models of nociception, the precise contribution of NO to nociception arising from hind paw incision is unknown, which is a rodent model of postoperative pain. In the present work, we have estimated the formation of NO in Sprague-Dawley rats, both at the site of incision and the corresponding spinal cord levels by Griess assay. Subsequently, naive rats were implanted with chronic indwelling intrathecal (i.t.) catheters. Fixed quantity (30 μg) of 1400 W, an iNOS inhibitor, was either administered locally into the wound at the time of incision or into the i.t. space, 15 min before hind paw incision. In a different set, i.t. 1400 W was administered, 20 h after incision. Control group received i.t. saline. Nociception was evaluated by guarding score, mechanical allodynia and thermal hyperalgesia. NO level was significantly increased between 4 h - day 1 locally and at 4 h at the spinal level after incision. Local inhibition of iNOS produced transient decrease of guarding (4-12 h) whereas pronounced decrease of guarding and allodynia was evident after spinal inhibition of iNOS. Also, spinal NO level decreased after i.t. drug administration. Post-incision drug treatment resulted in greater antinociceptive effect at day 1 though not on day 2. These results indicate involvement of NO in postincisional nociception in rats.

Somatostatin (SST) and the somatostatin receptor type 2 (sstr2) are expressed in the superficial part (Laminae I-III) of the dorsal horn of the spinal cord. Since the neurons in these laminae also receive nociceptive sensation from the periphery, it was hypothesized that both SST and sstr2 could be involved in the modulation of nociceptive transmission. To the best of knowledge, there are no studies on the involvement of SST and sstr2 in hind paw incision model in rats, which mimics postoperative pain in humans. Sprague-Dawley rats were subjected to hind paw incision under isoflurane anaesthesia and the resulting mechanical allodynia and thermal hyperalgesia were evaluated for 5 days. In another set of animals, the spinal cord was isolated at specified time intervals after incision and examined for SST and sstr2 expression using immunohistochemistry and immunoblotting procedures. Finally, nociceptive parameters were again evaluated in incised rats, which had received SST (400 µg/kg i.p. three times per day). Blood glucose level and locomotor activity were determined after SST treatment. Both allodynia and hyperalgesia were highest immediately after incision. Spinal SST expression increased at 2 h. A further increase was noted on day 3. Expression of sstr2 increased initially but decreased at day 1. These changes could be due to exocytosis of SST and internalization of the ligand-receptor complex. SST injection significantly attenuated mechanical allodynia but not thermal hyperalgesia. Significant change in blood glucose level or locomotor activity was absent. SST appears to contribute to postincisional pain. This finding could be of clinical relevance.

Wounds associated with injuries such as burns can produce moderate to severe pain. Besides causing distress to the patient, unrelieved pain could delay healing owing to stress‐related problems. Thus, pain needs to be treated as early as possible after injury. It was hypothesised that local treatment of wounds with appropriate analgesic drugs could attenuate pain. HOE 140, a bradykinin receptor antagonist, reduced acute inflammatory pain in rats after intrawound administration. In this study, the analgesic effect of dimethylsulphoxide (DMSO) was investigated in a similar hind‐paw incision model in rats. An extremely small quantity (10 µl) of 100% DMSO was administered into the incision site just before closure of the wound. It persistently attenuated guarding behaviour in rats over a period of 3 days without affecting thermal hyperalgesia or allodynia. Accumulated evidence indicates that guarding is equivalent to pain at rest in humans. The possible mechanisms of the analgesic effect could be inhibition of C group of peripheral nerve fibres or even free radical scavenging. Healing of the wound was found to be normal at the end of the study period. In conclusion, DMSO could be useful in the treatment of acute pain resulting from tissue injuries such as burns.

Background: Dorsal root ganglion (DRG) neurons mediate the transmission of sensation from the periphery. DRG neurons are pseudounipolar in nature and enveloped by the satellite glial cells (SC). Satellite glial cells have been reported to influence neuronal excitability via gap junctions. Postoperative pain causes induction of various neurotransmitters such as connexin-43 and glial fibrillary acidic protein (GFAP), in the satellite cells surrounding neuronal cell bodiesObjective: To study the expression of connexin-43 and Glial fibrillary acidic protein after hind paw incision.Methods: Male adult Sprague-Dawley rats (n=12) were used. Rats were randomly divided into two groups. Group I (n=6) and Group II (n=6) for immunohistochemical study with glial fibrillary acidic protein (GFAP) and connexin-43 (Cx-43) respectively. In this study, rats were subjected to noxious stimuli on the right hind paw under general anesthesia. Dorsal root ganglia of both sides (L4 spinal nerves) were isolated after transcardiac fixation with 4% paraformaldehyde. The ganglia from the non-incised side were taken as the control group.Results: Unipolar neurons in the DRG were surrounded by satellite cells. The satellite cells were positive for GFAP, which showed increased expression on the surgical side after noxious stimuli. Cx-43 immunostaining also showed an increased expression in the periphery of neuronal cell bodies of surgical side representing the location of gap junctions and hyperexcitability of neurons.Conclusions: Small to medium sized neurons carry pain sensation from the periphery to the central nervous system. Increased gap junctions were noted in small neurons and satellite cells after surgery. Gap junctions might contribute to increased excitability of small neurons in postoperative pain.

Objectives: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action. Methods: Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry. Results: Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1–4). Expression of SP was increased in the morphine + fosaprepitant group. Conclusions: The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.

Background & objectives: Treatment of inflammatory pain with opioids is accompanied by unpleasant and, at times, life-threatening side effects. Cannabis produces antinociception as well as psychotropic effects. It was hypothesized that peripheral cannabinoid receptors outside the central nervous system could be selectively activated for relief of pain. This study was undertaken to measure the antinociceptive effect of type 1 cannabinoid receptor (CB1r) agonist arachidonylcyclopropylamide (ACPA) in a rat model of inflammatory pain after intrawound administration and the effects were compared with lignocaine. Methods: Wounds were produced under controlled conditions by an incision in the right hind paw in rats. ACPA (10, 30 or 100 μg/10 μl) was administered directly into the wound. Antinociception was evaluated by guarding, allodynia and thermal hyperalgesia. This was compared to lignocaine (30 μg/10 μl). Reversal of ACPA (30 μg)-mediated antinociceptive effect was attempted by intrawound AM251 (100 μg), a CB1r antagonist. Antinociception was also evaluated after contralateral administration of ACPA (30 μg). Primary afferent nociceptive input to the spinal cord was investigated by c-Fos expression after ACPA treatment (100 μg). Results: ACPA, but not lignocaine, inhibited guarding behaviour, which was locally mediated. Conversely, lignocaine, but not ACPA, inhibited thermal hyperalgesia and mechanical allodynia. ACPA-mediated inhibitory effect was reversible and dose dependent. It was associated with a decreased c-Fos expression. Locomotor activity was unaffected following ACPA (100 μg) treatment. Interpretation & conclusions: Lignocaine attenuated evoked pain behaviour whereas ACPA decreased guarding score. This difference was likely due to blockade of sodium ion channels and the activation of peripheral CB1r, respectively. Central side effects were absent after ACPA treatment. Further studies need to be done to assess the effect of ACPA treatment in clinical conditions.