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

Acetate Causes Alcohol Hangover Headache in Rats

Background: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache. Methods: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats. Results: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate increased nociceptive behaviors suggesting that acetate, not acetaldehyde, accumulation results in hangover-like hypersensitivity in our model. Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity. Discussion: Our study shows that acetate contributes to hangover headache. These findings provide insight into the mechanism of hangover headache and the mechanism of headache induction

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