Post-infectious headache: a reactive headache?

Post-infectious disease syndrome includes both neurological and non-neurological disorders. However, headache as an isolated or a presenting complaint of post-infectious illness has not been well acknowledged in the literature. In this retrospective observation, patients having daily headache of more than 1 week and <4 weeks duration were included. We divided this group into patients having headache with preceding history of febrile illness in the recent past and patients without such history of febrile illness. We compared clinical features and therapeutic responses of various drugs between the groups. There were no significant differences in demographic features in these groups. However, associated neck pain, nausea, photophobia and meningeal signs were more prevalent in patients having history of preceding infection. A relatively lower proportion of subjects showed complete response to drugs at 3 months in post-infectious group. Good responses were noted to steroids in post-infectious group. In conclusion, a subset of patients with daily headache may be because of post-infectious pathology and treatment in the early stage may prevent it from becoming chronic. Large prospective studies are required to confirm these observations

The role of Cx36 and Cx43 in 4‐aminopyridine‐induced rhythmic activity in the spinal nociceptive dorsal horn: an electrophysiological study in vitro

Connexin (Cx) proteins and gap junctions support the formation of neuronal and glial syncytia that are linked to different forms of rhythmic firing and oscillatory activity in the CNS. In this study, quantitative reverse transcription polymerase chain reaction (RT‐qPCR) was used to profile developmental expression of two specific Cx proteins, namely glial Cx43 and neuronal Cx36, in postnatal lumbar spinal cord aged 4, 7, and 14 days. Extracellular electrophysiology was used to determine the contribution of Cx36 and Cx43 to a previously described form of 4‐aminopyridine (4‐AP)‐induced 4–12 Hz rhythmic activity within substantia gelatinosa (SG) of rat neonatal dorsal horn (DH) in vitro. The involvement of Cx36 and Cx43 was probed pharmacologically using quinine, a specific uncoupler of Cx36 and the mimetic peptide blocker Gap 26 which targets Cx43. After establishment of 4–12 Hz rhythmic activity by 4‐AP (25 μmol/L), coapplication of quinine (250 μmol/L) reduced 4‐AP‐induced 4–12 Hz rhythmic activity (P < 0.05). Preincubation of spinal cord slices with Gap 26 (100 μmol/L), compromised the level of 4‐AP‐induced 4–12 Hz rhythmic activity in comparison with control slices preincubated in ACSF alone (P < 0.05). Conversely, the nonselective gap junction “opener” trimethylamine (TMA) enhanced 4–12 Hz rhythmic behavior (P < 0.05), further supporting a role for Cx proteins and gap junctions. These data have defined a physiological role for Cx36 and Cx43 in rhythmic firing in SG, a key nociceptive processing area of DH. The significance of these data in the context of pain and Cx proteins as a future analgesic drug target requires further study

Improvement of the Trivalent Inactivated Flu Vaccine Using PapMV Nanoparticles

Commercial seasonal flu vaccines induce production of antibodies directed mostly towards hemaglutinin (HA). Because HA changes rapidly in the circulating virus, the protection remains partial. Several conserved viral proteins, e.g., nucleocapsid (NP) and matrix proteins (M1), are present in the vaccine, but are not immunogenic. To improve the protection provided by these vaccines, we used nanoparticles made of the coat protein of a plant virus (papaya mosaic virus; PapMV) as an adjuvant. Immunization of mice and ferrets with the adjuvanted formulation increased the magnitude and breadth of the humoral response to NP and to highly conserved regions of HA. They also triggered a cellular mediated immune response to NP and M1, and long-lasting protection in animals challenged with a heterosubtypic influenza strain (WSN/33). Thus, seasonal flu vaccine adjuvanted with PapMV nanoparticles can induce universal protection to influenza, which is a major advancement when facing a pandemic

A low cortisol response to stress is associated with musculoskeletal pain combined with increased pain sensitivity in young adults: A longitudinal cohort study

Background: In this study, we investigated whether an abnormal hypothalamic-pituitary-adrenal (HPA) axis response to psychosocial stress at 18 years of age is associated with musculoskeletal (MS) pain alone and MS pain combined with increased pain sensitivity at 22 years of age. Methods: The study sample included 805 participants from the Western Australian Pregnancy Cohort (Raine) Study who participated in the Trier Social Stress Test (TSST) at age 18 years. Number of pain sites, pain duration, pain intensity and pain frequency were assessed at age 22 to measure severity of MS pain. Cold and pressure pain thresholds were determined at age 22. Group-based trajectory modeling was applied to establish cortisol response patterns based on the TSST. Logistic regression was used to study the association of TSST patterns with MS pain alone and MS pain combined with increased cold or pressure pain sensitivity, adjusted for relevant confounding factors. All analyses were stratified by sex. Results: The mean (standard deviation) age during the TSST was 18.3 (0.3) years, and during MS pain assessment it was 22.2 (0.6). Forty-five percent of the participants were female. Three cortisol response patterns were identified, with cluster 1 (34 % of females, 21 % of males) reflecting hyporesponse, cluster 2 (47 %, 54 %) reflecting intermediate response and cluster 3 (18 %, 24 %) reflecting hyperresponse of the HPA axis. MS pain was reported by 42 % of females and 33 % of males at age 22 years. Compared with females in cluster 2, females in cluster 1 had an increased likelihood of having any MS pain (odds ratio 2.3, 95 % confidence interval 1.0-5.0) and more severe MS pain (2.8, 1.1-6.8) if their cold pain threshold was above the median. In addition, females in cluster 1 had an increased likelihood (3.5, 1.3-9.7) of having more severe MS pain if their pressure pain threshold was below the median. No statistically significant associations were observed in males. Conclusions: This study suggests that a hyporesponsive HPA axis at age 18 years is associated with MS pain at 22 years in young females with increased pain sensitivity

Selective P2X7 receptor antagonists for chronic inflammation and pain

ATP, acting on P2X7 receptors, stimulates changes in intracellular calcium concentrations, maturation, and release of interleukin-1β (IL-1β), and following prolonged agonist exposure, cell death. The functional effects of P2X7 receptor activation facilitate several proinflammatory processes associated with arthritis. Within the nervous system, these proinflammatory processes may also contribute to the development and maintenance of chronic pain. Emerging data from genetic knockout studies have indicated specific roles for P2X7 receptors in inflammatory and neuropathic pain states. The discovery of multiple distinct chemical series of potent and highly selective P2X7 receptor antagonists have enhanced our understanding of P2X7 receptor pharmacology and the diverse array of P2X7 receptor signaling mechanisms. These antagonists have provided mechanistic insight into the role(s) P2X7 receptors play under pathophysiological conditions. In this review, we integrate the recent discoveries of novel P2X7 receptor-selective antagonists with a brief update on P2X7 receptor pharmacology and its therapeutic potential

P2Y receptors and pain transmission

It is widely accepted that the most important ATP receptors involved in pain transmission belong to the P2X3 and P2X2/3 subtypes, selectively expressed in small diameter dorsal root ganglion (DRG) neurons. However, several types of the metabotropic ATP (P2Y) receptors have also been found in primary afferent neurons; P2Y1 and P2Y2 receptors are typically expressed in small, nociceptive cells. Here we review the results available on the involvement of P2Y receptors in the modulation of pain transmission

An evaluation of immune function and effects of fluoxetine in rodent models of depressive and sickness behavior

Several lines of research have identified similarities between behaviors associated with major depressive disorder (MDD) and those associated with immune activation, referred to as sickness behaviors. Reports of altered immune parameters in MDD patients further point to a shared mechanism underlying depressive and sickness behaviors. Most reliable of these immune changes are suppressed natural killer cell activity (NKCA) and alterations in leukocyte subsets. Further, some studies have demonstrated that treatment of MDD with the selective serotonergic reuptake inhibitors (SSRIs) increase NKCA in a subset of depressed patients. In light of these findings the following questions were posed: (1) Is sickness behavior induced by animal models of depressive states? (2) Is NKCA suppression observed in rodent models of MDD, and is this reduction reversible by SSRI administration? (3) Does repeated immune activation induce depressive behaviors and the immune alterations observed in MDD patients, and does SSRI administration restore these alterations? Behavioral similarities between depressive and sickness behaviors, and immune alterations associated with MDD suggest that immune activation leads to depressive behaviors. The immune alterations found with MDD are also associated with the release of proinflammatory cytokines from activated macrophages which have been implicated in sickness behavior and hypothalamic-pituitary-adrenal (HPA) axis activation. Administration of proinflammatory mediators to non-depressed patients induces depressive symptoms and increases HPA axis activity. HPA axis activation is associated with MDD and is modulated by SSRIs. Further, SSRIs have been shown to suppress macrophage function. Chronic mild stress (CMS) in rodents is used to model MDD, and elicits depressive behaviors and increases HPA axis activity. With the questions above, the following hypotheses were tested: (1) CMS and repeated immune activation with zymosan (yeast cell wall mannoprotein) will have similar and parallel effects on depressive behaviors measured in Porsolt\u27s forced swim test and on sickness behaviors defined by the social investigation task; (2) Both CMS and repeated immune activation will activate the HPA axis evidenced by elevated circulating corticosterone; (3) Both CMS and repeated immune activation will disrupt innate immune function measured by decreased NKCA and macrophage activation evidenced by increased intracellular ROS; and (4) chronic fluoxetine will normalize behavior, endocrine, and immune responses. CMS suppressed NKCA, and consistent with findings in MDD patients, chronic fluoxetine abrogated CMS-induced suppression of NKCA. Furthermore, CMS stimulated macrophage activity as evidenced by increased ROS, which was not altered by fluoxetine. Taken together these findings suggest that the CMS model is an appropriate model to further explore the relationship between depressive behaviors and related immune function. In contrast, chronic zymosan did not alter immune measures. Both CMS and chronic zymosan induced depressive behaviors, however neither manipulation induced sickness behavior. While previous studies have evaluated acute pathogen administration, given the chronic nature of MDD, the current study used repeated administration of pathogen. This may account for the differences with previous research. FLX did not reverse behavior alterations induced by chronic zymosan