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Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring ≤5 minutes after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.

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Rationale: It has been nearly 20 years since sarcoidosis mortality was examined at the population level in the United States. Objectives: To examine mortality rates and underlying causes of death among United States decedents with sarcoidosis from [1988][1989][1990][1991][1992][1993][1994][1995][1996][1997][1998][1999][2000][2001][2002][2003][2004][2005][2006][2007]. Methods: We used data from the National Center for Health Statistics to (1) calculate age-adjusted sarcoidosis-associated mortality rates; (2) examine how those rates differ by age, sex, and race and ethnicity; and (3) determine underlying causes of death among sarcoidosis decedents. Measurements and Main Results: From 1988 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Over this time, the age-adjusted, sarcoidosis-related mortality rate increased 50.5% in women and 30.1% in men. The greatest absolute increase in death rates was among non-Hispanic black females. Regardless of sex or race, mortality rates climbed most in decedents 55 years or older. The most common cause of death was sarcoidosis itself. Younger sarcoidosis decedents with pulmonary fibrosis were more likely to be black than white, and younger sarcoidosis decedents were more likely than similarly aged decedents in the general population to have a cardiac cause contribute to death. Conclusions: From 1988-2007, sarcoidosis-related mortality rates increased significantly, particularly in non-Hispanic black females aged 55 years or older. The underlying cause of death in most patients with sarcoidosis was the disease itself. Among young sarcoidosis decedents, those with pulmonary fibrosis or a cardiac cause contributing to death were more likely to be black than white.Keywords: sarcoidosis; mortality; epidemiology Sarcoidosis is a multisystem, granulomatous disease of unknown cause (1) that most commonly affects young adults, particularly females (2). Sarcoidosis affects the thorax (lungs or mediastinal lymph nodes) in more than 90% of patients (3). Worldwide, the highest annual incidence of sarcoidosis (5-40 cases per 100,000 population) has consistently been observed in northern European countries (4). In the United States, the adjusted annual incidence of sarcoidosis is over three times greater in blacks than whites (35.5 cases vs. 10.9 cases per 100,000 population) (4). In the Black Women's Health Study, a study that enrolled a cohort of 59,000 black United States women, investigators calculated an annual incidence rate of 71 per 100,000 (5). Black Americans with sarcoidosis are more likely than other racial groups in the United States to suffer extrathoracic organ (e.g., skin or eye) involvement and a chronic disease course (3, 6).For most patients, sarcoidosis is a benign disorder; many never develop clinically significant disease, and spontaneous remission is not infrequent (6, 7). However, for a significant minority of patients, sarcoidosis is a chronic, debilitating, and even life-threatening condition: investigators have r...