Nociceptive neuropeptide increases and periorbital allodynia in a model of traumatic brain injury.

OBJECTIVE: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. METHODS: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. RESULTS: Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P \u3c .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P \u3c .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P \u3c .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P \u3c .0001. There was a significant correlation between CGRP and periorbital allodynia (P \u3c .0001, r = -0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks post-injury, P \u3c .001. GFAP(+) immunoreactivity was significantly increased at 7 but not 14 or 28 days after CCI, P \u3c .001. Craniotomy resulted in transient periorbital allodynia accompanied by transient increases in SP, CGRP, and GFAP immunoreactivity compared with control mice. There was no increase in the number of macrophage/microglia cells compared with controls after craniotomy. CONCLUSION: Injury to the somatosensory cortex results in persistent periorbital allodynia and increases in brainstem nociceptive neuropeptides. Findings suggest that persistent allodynia and increased neuropeptides are maintained by mechanisms other than activation of macrophage/microglia or astrocyte in the injured somatosensory cortex

Is phonophobia associated with cutaneous allodynia in migraine?

ABSTRACT Objective To determine whether phonophobia and dynamic mechanical (brush) allodynia are associated in episodic migraine (EM). Methods Adult patients with EM were prospectively recruited. A structured questionnaire was used to obtain demographic and migraine related data. Phonophobia was tested quantitatively using a real time sound processor and psychoacoustic software. Sound stimuli were pure tones at frequencies of 1000 Hz, 4000 Hz and 8000 Hz, delivered to both ears at increasing intensities, until an aversive level was reached. Allodynia was assessed by brushing the patient’s skin with a gauze pad at different areas. Patients were tested both between and during acute attacks. Sound aversion thresholds (SATs) in allodynic and non-allodynic patients were compared. Results Between attacks, SATs were lower in allodynic compared with non-allodynic patients, with an average difference of 5.7 dB (p¼0.04). During acute attacks, the corresponding average SAT difference (allodynicenon-allodynic) was 15.7 dB (p¼0.0008). There was a significant negative correlation between allodynia scores and SATs, both within and between attacks. Conclusions The results support an association between phonophobia and cutaneous allodynia in migraine

Histo-Blood Group Antigen Null Phenotypes Associated With a Decreased Risk of Clinical Rotavirus Vaccine Failure Among Children <2 Years of Age Participating in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in Kenya, Mali, and the Gambia

Background: Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children 4. Conclusions: Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness

The Role of Adenosine Signaling in Headache: A Review

Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine

Diseases, disorders, and comorbidities of interoception

Interoception, the sense of the body's internal physiological state, underpins homeostatic reflexes, motivational states, and sensations contributing to emotional experiences. The continuous nature of interoceptive processing, coupled to behavior, is implicated in the neurobiological construction of the sense of self. Aberrant integration and control of interoceptive signals, originating in the brain and/or the periphery, can perturb the whole system. Interoceptive abnormalities are implicated in the pathophysiology of psychiatric disorders and in the symptomatic expression of developmental, neurodegenerative, and neurological disorders. Moreover, interoceptive mechanisms appear central to somatic disorders of brain–body interactions, including functional digestive disorders, chronic pain, and comorbid conditions. The present article provides an overview of disorders of interoception and suggests future directions for better understanding, diagnosis, and management of these disorders

The (R)- isomer of isometheptene decreases trigeminal sensitivity in a rat model of primary headache

Introduction Isometheptene is thought to be the active ingredient of the commonly known headache medication, Midrin. Previously, we found only the (R) enantiomer to be effective in alleviating headache behavior in two models of headache compared to the (S) enantiomer. Experiments using electrical and mechanical stimulation of the dura in animals with no history of head pain have been used to elucidate the mechanisms of the trigeminovascular system at the level of the trigeminal ganglion, trigeminal nucleus caudalis, periaqueductal gray, and the thalamus. The limitation of these acute models is that electrical and mechanical stimulation of the dural blood vessels does not cause long lasting pain similar to recurrent headache pain in humans. Two animal models for the investigation of headache pathophysiology that include aspects of the chronic nature of headache were included in this study. These models provide a new approach to study the pathophysiology of recurrent headache and support validation of novel treatments. Using behavior methods of monitoring trigeminal allodynia in rats, our group discovered a rat with spontaneous episodic trigeminal allodynia (STA) (Oshinsky et al, 2012). The model was established through 18 generations of inbreeding for testing analgesics and the further understanding of mechanisms of migraine. STA rats experience similar symptoms to human migraine patients, such as episodic trigeminal sensitivity, phonophobia, responsiveness to abortive and prophylactic headache treatments, and sensitivity to migraine triggers. A second well-characterized model of repeated dural inflammatory stimulation (IS), in which an inflammatory stimulant is infused over the dura, also results in persistent headache behavior that has been accepted as a valid model for drug testing. Although the pathological mechanisms between the two models are different, one being considered idiopathic or a spontaneous model and the other inflammatory in nature, the precise mechanism(s) remain elusive. The aim of this study is to determine the dose response of the (R)-isomer of isometheptene on trigeminal sensitivity in the STA and IS rat models and study the mechanism of action of isometheptene. Poster presented at: American Headache Society 58th Annual Scientific Meeting in San Diego CA.https://jdc.jefferson.edu/neurosurgeryposters/1005/thumbnail.jp