Propranolol treatment prevents chronic central sensitization induced by repeated dural stimulation.

Migraine is currently conceptualized as a chronic disease with episodic manifestations. In some patients, migraine attack frequency increases, leading to chronic migraine. Daily preventive therapy is initiated to decrease attack frequency. Propranolol, a first-line medication for migraine prophylaxis, reduces attack frequency in nearly 50% of patients receiving it. However, the mechanisms of its antimigraine action are unclear. We examined the effect of daily propranolol treatment (10 mg·kg per os, 8 days) in a rat model of recurrent activation of dural nociceptors (repeated infusion of an inflammatory soup (IS) on the dura through a cannula every 2-3 days). Propranolol does not abort IS-induced acute cephalic mechanical allodynia but blocks the development of a chronic cutaneous hypersensitivity upon repeated IS injections. Furthermore, propranolol prevents (1) the elevated touch-evoked Fos expression within the trigeminocervical complex, (2) enhanced both spontaneous activity, and evoked responses of second-order trigeminovascular neurons, (3) elevated touch-evoked rostral ventromedial medulla and locus coeruleus Fos expression and (4) diffuse noxious inhibitory controls impairment, induced by repeated IS injections. Our results suggest that propranolol exerts its prophylactic action, at least in part, by blocking the chronic sensitization of descending controls of pain, arising from the rostral ventromedial medulla and locus coeruleus, and in turn preventing the maintenance of a state of facilitated trigeminovascular transmission within the trigeminocervical complex. Assessing changes in these brain areas has the potential to elucidate the mechanisms for migraine transformation and to reveal novel biological and molecular targets for specific migraine-preventive therapies.

General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression.

Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low- and high-intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high-intensity, but not low-intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low-intensity stimulation, too, induces a reversible cephalic allodynia, and high-intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high-intensity stimulation. Fos expression reveals that a single high-intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition-induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine.

Personality, space use and tick load in an introduced population of Siberian chipmunks Tamias sibiricus.

1. Although behaviours can contribute to the heterogeneity in parasite load among hosts, links between consistent individual differences in behaviour and parasitic infection have received little attention. We investigated the role of host activity and exploration on hard tick infestations of marked individuals in a population of Siberian chipmunks Tamias sibiricus introduced in a suburban French forest over 3 years. 2. Individual activity-exploration profiles were assessed from 106 hole-board tests on 73 individuals, and chipmunks' trappability and trap diversity were used respectively as indices of their activity-exploration and space use on a sub-sample of 60 individuals. At each capture, we counted the total number of ticks per head of chipmunk. 3. We found significant and consistent individual differences in activity-exploration, trappability, trap diversity and tick load, and could estimate individual indices for these four variables, corrected for confounding effects of year, season, body mass and sex. 4. Using a path analysis, we found an indirect effect of activity-exploration on tick load: tick load increased with space use, which in turn was positively affected by trappability in the field. Trappability was itself positively related to activity-exploration in the hole board. Habitat type affected tick load, independently of behavioural traits. A second path model revealed a lack of either direct or indirect influence of tick loads on chipmunks' personality and trappability. 5. Our results show that host personality-related patterns in space use can lead to a non-random parasite distribution among hosts.