Normal cerebrospinal fluid levels of hypocretin-1 (orexin A) in patients with fibromyalgia syndrome.

BACKGROUND: The hypothalamic neuropeptide hypocretin (orexin) modulates sleep-wake, feeding and endocrine functions. Cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) concentrations are low in patients with narcolepsy-cataplexy, a sleep disorder characterized by hypersomnolence and rapid eye movement (REM) sleep abnormalities. METHODS: We determined CSF Hcrt-1 concentrations of patients with the fibromyalgia syndrome (FMS), a condition characterized by fatigue, insomnia and in some cases daytime hypersomnolence. RESULTS: Basal CSF levels of Hcrt-1 in FMS did not differ from those in healthy normal controls. CONCLUSIONS: These findings suggest that abnormally low Hcrt-1 is not a likely cause of fatigue in FMS.

Chronic daily intrathecal injections of a large volume of fluid increase mast cells in the thalamus of mice.

Mast cells are found in the central nervous system (CNS) as well as in the periphery. In the brain of mice, they are localized primarily in the thalamus and meninges. Although their numbers increase in response to stress, the mediator of their recruitment is not known. During studies in which drugs were delivered intrathecally in a volume sufficiently large to distribute to the brain, we discovered that repeated daily injections of this large volume increased the number of mast cells in the thalamus. The increase was not due to changes in electrolyte composition of the cerebrospinal fluid (CSF) as chronically administered artificial CSF produced similar effects. Repeated injections of even small volumes (2 mul) increased mast cells in the medial intralaminar (Med), ventral posterior (VP) and posterior (Po) nuclei. Increasing the volume injected daily to 20 mul increased mast cells in the lateral intralaminar (Lat), laterodorsal (LD), ventrolateral (VL) and lateral geniculate (LG) nuclei and further increased those in the lateral extension of the Po nucleus. Thus, small and large volumes augment distinct populations of mast cells. While stem cell factor (SCF) is abundant in the CNS and is chemotactic to mast cells in the periphery, thalamic mast cells in the rodent do not express c-kit, the SCF receptor, suggesting that this factor may not be responsible for the effect. Consistent with this, centrally injected SCF was incapable of increasing thalamic mast cell populations after either single or chronic (21 days) daily injections compared to the effect of saline alone. Although the mechanism is not known, repeated injections of a large volume of fluid dramatically increase mast cells in the CNS, a phenomenon that may be relevant to clinical conditions of increased CSF pressure or volume.

Unilateral spinal nerve ligation leads to an asymmetrical distribution of mast cells in the thalamus of female but not male mice.

Mast cells are restricted to the leptomeninges and thalamus of healthy mice. These populations are increased by stress and highly sensitive to reproductive hormones. To examine the influence of nociception, a form of stress, on thalamic mast cells, we ligated the left fifth lumbar spinal nerve of male and female mice to induce hyperalgesia. Two, 7 and 14 days later, mice were killed and thalami examined histologically using toluidine blue stain. The total number of thalamic mast cells was not influenced by ligation of the spinal nerve compared to sham-operation in either female or male mice. However, in females, the percent of thalamic mast cells located on the side of the thalamus contralateral to the ligation was greater on days 2 and 7, coincident with mechanical hyperalgesia. At these times, areas in which mast cells were most dense contralateral to nerve-injury included the posterior (Po) and lateral geniculate (LG) nuclei compared to their symmetrical distribution in sham-operated mice. These data suggest that local nociceptive signals to each side of the thalamus rather than stress hormones influence the location of mast cells during the development of allodynia and hyperalgesia. In addition, both hyperalgesia and mast cell distribution induced by nerve-ligation differ in females compared to males, reflecting a novel neuroimmune response to pain within the CNS.

Naloxone-induced morphine withdrawal increases the number and degranulation of mast cells in the thalamus of the mouse.

Naloxone-induced jumping in morphine-dependent mice is inhibited by cromolyn, a mast cell stabilizer, suggesting that this characteristic withdrawal behavior results from degranulation of mast cells. Because withdrawal is considered as a central phenomenon, degranulation of mast cells located within the CNS may influence aspects of opioid withdrawal. The present study evaluates histologically whether naloxone, injected into opioid dependent mice, induces degranulation of mast cells. Seventy-two hours after the s.c. implantation of a 75 mg morphine pellet, the number and degranulation of thalamic mast cells did not differ from those in placebo-implanted controls. However, two injections of 50 mg/kg of naloxone, 30 and 60 min before tissue collection, increased the number of degranulated mast cells compared to those in mice injected with saline. Analysis throughout the entire thalamus (90 40-micro sections) revealed increases in the total number of mast cells as well as the number that were degranulated, especially in sections 52-60, corresponding to Bregma -2.18 to 2.54. Here, mast cells were clustered in the IGL and VPL/VPM nuclei, and redistributed from the ventromedial to the dorsolateral aspects of the Po and PF nuclei during withdrawal. Degranulation was also greater throughout the LD, LP nuclei during withdrawal. These data reveal a novel neuroimmune reaction to opioid withdrawal in the CNS.

Antihyperalgesic effects of intrathecal neuropeptide Y during inflammation are mediated by Y1 receptors.

Inflammation induces an up-regulation of neuropeptide tyrosine (NPY) and its receptors in the dorsal horn, suggesting an important role in nociceptive transmission. Our initial studies revealed that NPY dose-dependently increased hotplate response latency, and to a lesser degree, thermal paw withdrawal latency (PWL); these effects occurred at doses that affect neither motor coordination (as assessed by the rotarod test) nor paw skin temperature. We next evaluated the behavioral effects of intrathecal administration of NPY and NPY antagonists with the aim of assessing the contribution of NPY to correlates of persistent nociception associated with the unilateral plantar injection of carrageenan or complete Freund's adjuvant (CFA). NPY robustly and dose-dependently increased PWL on the side ipsilateral to carrageenan injection, with only a small effect on the contralateral side. Similarly, NPY (30 microg) produced a large and long-lasting increase in PWL on the side ipsilateral to CFA injection (140% change), with only a small effect on the contralateral side (25% change). The ipsilateral effect of NPY was completely inhibited with the potent Y1 antagonist, BIBO 3304 (3 microg), but not the Y2 antagonist, BIIE 0246. When administered alone, BIBO 3304 (but not BIIE 0246) slightly decreased thermal PWL on the side ipsilateral (25% change), but not contralateral, to CFA injection; this suggests that inflammation strengthens inhibitory NPY tone. We conclude that spinal Y1 receptors contribute to the inhibitory effects of NPY on thermal hypersensitivity in the awake rat. Further studies are necessary to determine whether enhanced release of NPY and Y1-mediated inhibition of spinal nociceptive transmission ultimately results in a compensatory, adaptive inhibition of thermal hypersensitivity in the setting of inflammation.