Abstract:

Abstract:
Chronic facial pain, a frequent and disabling condition, is maintained by central sensitization, which results in pain hypersensitivity. Although it is well established that reactive astrocytes play a key role in persistent pain mechanisms, the role of disruption of the normal capacity of astrocytes to maintain neuronal homeostasis is much less known. Here we show that persistent facial inflammation disturbs potassium homeostasis in the medullary dorsal horn of male rats, due to a sex-specific, drastic downregulation of astroglial inward rectifier potassium Kir4.1 channels. Using selective genetic tools, we establish that such downregulation, likely due to the release of IL-1beta during inflammatory processing, is sufficient and required to drive pain hypersensitivity through altered K+ baseline levels. We further show that this chain of events can be prevented by selective upregulation of astroglial Kir4.1, or through systemic administration of 5-azacytidine, a DNA methylation modulator. Our results thus reveal a critical mechanism by which astrocyte dysfunction drives persistent inflammatory facial pain in males and discover the therapeutic potential of targeting central Kir4.1 for treating this disease.

Abstract:
Chronic pain is a frequent and disabling condition that is significantly maintained by central sensitization, which results in pathological amplification of responses to noxious and innocuous stimuli. As such, mechanical allodynia, or pain in response to a tactile stimulus that does not normally provoke pain, is a cardinal feature of chronic pain. Recent evidence suggests that the dorsal horn excitatory interneurons that express the gamma isoform of protein kinase C (PKCgamma) play a critical role in the mechanism of mechanical allodynia during chronic pain. Here, we review this evidence as well as the main aspects of the development, anatomy, electrophysiology, inputs, outputs, and pathophysiology of dorsal horn PKCgamma neurons. Primary afferent high-threshold neurons transmit the nociceptive message to the dorsal horn of the spinal cord and trigeminal system where it activates second-order nociceptive neurons relaying the information to the brain. In physiological conditions, low-threshold mechanoreceptor inputs activate inhibitory interneurons in the dorsal horn, which may control activation of second-order nociceptive neurons. During chronic pain, low-threshold mechanoreceptor inputs now activate PKCgamma neurons that forward the message to second-order nociceptive neurons, turning thus tactile inputs into pain. Several mechanisms may contribute to opening this gate, including disinhibition, activation of local astrocytes, release of diffusible factors such as reactive oxygen species, and alteration of the descending serotoninergic control on PKCgamma neurons through 5-HT2A serotonin receptors. Dorsal horn PKCgamma neurons, therefore, appear as a relevant therapeutic target to alleviate mechanical allodynia during chronic pain.

Abstract:
Background This study investigated the effects of medication overuse and withdrawal on modulation of pain processing in women with migraine. Temporal summation of laser-evoked thermal pain was used to measure the effects of conditioned pain modulation. Methods 36 female participants (12 healthy volunteers, 12 with episodic migraine and 12 with medication overuse headache) were included in a two session protocol. Medication overuse headache subjects were also tested three weeks after medication overuse headache withdrawal. Mechanical and laser-evoked thermal pain thresholds were measured on the back of the non-dominant hand where, later, temporal summation of laser-evoked thermal pain to repetitive thermal stimuli was elicited for 30 min, at an intensity producing moderate pain. Between the 10th and 20th minutes, the contralateral foot was immersed into a water bath at a not painful (30) or painfully cold (8; conditioned pain modulation) temperature. Results Episodic migraine, medication overuse headache and medication overuse headache withdrawal were associated with an increase in extracephalic temporal summation of laser-evoked thermal pain as compared to healthy volunteer subjects, while there was no alteration of laser-evoked thermal and mechanical extracephalic pain thresholds in these subjects. Conditioned pain modulation was highly efficient in temporal summation of laser-evoked thermal pain in healthy volunteer subjects, with a solid post-effect (reduction of pain). Conditioned pain modulation was still present, but reduced, in episodic migraine. By contrast, conditioned pain modulation was normal in medication overuse headache and strongly reduced in medication overuse headache withdrawal. Furthermore, in medication overuse headache withdrawal, the post-effect was no longer a decrease, but a facilitation of pain. Conclusions These data show that a decrease in conditioned pain modulation does not underlie medication overuse headache in women. On the contrary, medication overuse reinstated conditioned pain modulation in female migraine patients. They also identify different phenotypes of pain modulation in migraine patients. Registration number N degrees 2008-A00471-54.

Abstract:
Fluoroacetate has been widely used to inhibit glia metabolism in vivo. It has yet to be shown what the effects of chronic intrathecal infusion of fluoroacetate on nociceptive behavioral testing are. The effects of chronic infusion of fluoroacetate (5 nmoles/h) for 2 weeks were examined in normal rats. Chronic intrathecal fluoroacetate did not alter mechanical threshold (von Frey filaments), responses to supra-threshold mechanical stimuli (von Frey filaments), responses to hot (hot plate) or cool (acetone test) stimuli and did not affect motor performance of the animals, which was tested with rotarod. This suggests that fluoroacetate at appropriate dose did not suppress neuronal activity in the spinal cord.

Abstract:
Thirst and antidiuretic hormone secretion occur during hyperthermia or hypertonicity to preserve body hydration. These vital responses are triggered when hypothalamic osmoregulatory neurons become depolarized by ion channels encoded by an unknown product of the transient receptor potential vanilloid-1 gene (Trpv1). Here, we show that rodent osmoregulatory neurons express a transcript of Trpv1 that mediates the selective translation of a TRPV1 variant that lacks a significant portion of the channel's amino terminus (DeltaN-TRPV1). The mRNA transcript encoding this variant (Trpv1dn) is widely expressed in the brains of osmoregulating vertebrates, including the human hypothalamus. Transfection of Trpv1dn into heterologous cells induced the expression of ion channels that could be activated by either hypertonicity or by heating in the physiological range. Moreover, expression of Trpv1dn rescued the osmosensory and thermosensory responses of single hypothalamic neurons obtained from Trpv1 knockout mice. DeltaN-TRPV1 is therefore a co-detector of core body temperature and fluid tonicity.

Abstract:
Activation of N-methyl-d-aspartate (NMDA) receptors is critical for hypersensitivity in chronic neuropathic pain. Since astroglia can regulate NMDA receptor activation by releasing the NMDA receptor co-agonist d-serine, we investigated the role of NMDA receptor and d-serine in neuropathic chronic pain. Male Wistar rats underwent right L5-L6 spinal nerve ligation or sham surgery and were tested for mechanical allodynia and hyperalgesia after 14 days. Acute intrathecal administration of the NMDA receptor antagonist AP-5 as well as chronic administration of the glia metabolism inhibitor fluoroacetate significantly reduced mechanical allodynia in neuropathic rats. The effect of fluoroacetate was reversed by acutely administered intrathecal d-serine. Degrading d-serine using acute intrathecal administration of d-aminoacid oxidase also reduced pain symptoms. Immunocytochemistry showed that about 70% of serine racemase, the synthesizing enzyme of d-serine, was expressed in astrocyte processes in the superficial laminae of L5 dorsal horn. Serine racemase expression was upregulated in astrocyte processes in neuropathic rats compared to sham rats. These results show that neuropathic pain depends upon glial d-serine that co-activates spinal NMDA receptors.

Abstract:
The mechanisms by which dietary salt promotes hypertension are unknown. Previous work established that plasma [Na(+)] and osmolality rise in proportion with salt intake and thus promote release of vasopressin (VP) from the neurohypophysis. Although high levels of circulating VP can increase blood pressure, this effect is normally prevented by a potent GABAergic inhibition of VP neurons by aortic baroreceptors. Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain-derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling. We show that high salt intake increases the spontaneous firing rate of VP neurons in vivo and that circulating VP contributes significantly to the elevation of arterial pressure under these conditions. These results provide the first demonstration that dietary salt can affect blood pressure through neurotrophin-induced plasticity in a central homeostatic circuit.

Abstract:

Abstract:
Bone cancer pain is a common and disruptive symptom in cancer patients. In cancer pain animal models, massive reactive astrogliosis in the dorsal horn of the spinal cord has been reported. Because astrocytes may behave as driving partners for pathological pain, we investigated the temporal development of pain behavior and reactive astrogliosis in a rat bone cancer pain model induced by injecting MRMT-1 rat mammary gland carcinoma cells into the tibia. Along with the development of bone lesions, a gradual mechanical and thermal allodynia and hyperalgesia as well as a reduced use of the affected limb developed in bone cancer-bearing animals, but not in sham-treated animals. Dorsal horn Fos expression after nonpainful palpation of the injected limb was also increased in bone cancer-bearing animals. However, at any time during the evolution of tumor, there was no increase in glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn. Further analysis at 21days after injection of the tumor showed no increase in GFAP and interleukin (IL) 1beta transcripts, number of superficial dorsal horn S100beta protein immunoreactive astrocytes, or immunoreactivity for microglial markers (OX-42 and Iba-1). In contrast, all these parameters were increased in the dorsal horn of rats 2weeks after sciatic nerve ligation. This suggests that in some cases, bone cancer pain may not be correlated with spinal overexpression of reactive glia markers, whereas neuropathic pain is. Glia may thus play different roles in the development and maintenance of chronic pain in these 2 situations.