Decreased Central μ-Opioid Receptor Availability in Fibromyalgia

Harris, Richard E.; Clauw, Daniel J.; Scott, David J.; McLean, Samuel A.; Gracely, Richard H.; Zubieta, Jon Kar

doi:10.1523/jneurosci.2849-07.2007

Cited by 448 publications

(307 citation statements)

References 43 publications

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“…In support of this interpretation are findings in healthy subjects demonstrating that reward responsiveness is correlated with magnitude of opioid analgesia and predicts neural activity in the nucleus accumbens (Wanigasekera et al, 2012). Previous studies have shown that PCP have abnormal opioid systems (Harris et al, 2007) and in the clinic, these patients frequently show reduced response to opioids (Manchikanti et al, 2011). During chronification of pain, changes in the opioid and dopamine systems are accompanied by changes in neuronal activity and connectivity in an animal models of neuropathic pain (Chang et al, 2014), consistent with cross-sectional and longitudinal studies in humans with chronic pain (Baliki et al, 2012).…”

Section: Discussionmentioning

confidence: 85%

Reward responsiveness in patients with chronic pain

Elvemo

Landrø

Borchgrevink

et al. 2015

European Journal of Pain

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Background: It is proposed that changes in reward processing in the brain are involved in the pathophysiology of pain based on experimental studies. The first aim of the present study was to investigate if reward drive and/or reward responsiveness was altered in patients with chronic pain (PCP) compared to controls matched for education, age and sex. The second aim was to investigate the relationship between reward processing and nucleus accumbens volume in PCP and controls. Nucleus accumbens is central in reward processing and its structure has been shown to be affected by chronic pain conditions in previous studies. Methods: Reward drive and responsiveness were assessed with the Behavioral Inhibition Scale/Behavioral Activation Scale, and nucleus accumbens volumes obtained from T1-weighted brain MRIs obtained at 3T in 19 PCP of heterogeneous aetiologies and 20 age-, sex-and education-matched healthy controls. Anhedonia was assessed with Beck's Depression Inventory II. Results: The PCP group had significantly reduced scores on the reward responsiveness, but not reward drive. There was a trend towards smaller nucleus accumbens volume in the PCP compared to control group. There was a significant positive partial correlation between reward responsiveness and nucleus accumbens volume in the PCP group adjusted for anhedonia, which was significantly different from the same relationship in the control group. Conclusions: Reward responsiveness is reduced in chronic pain patients of heterogeneous aetiology, and this reduction was associated with nucleus accumbens volume. Reduced reward responsiveness could be a marker of chronic pain vulnerability, and may indicate reduced opioid function.

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Section: Discussionmentioning

confidence: 85%

Reward responsiveness in patients with chronic pain

Elvemo

Landrø

Borchgrevink

et al. 2015

European Journal of Pain

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“…Participant inclusion and exclusion criteria have been reported previously (5). All participants met the American College of Rheumatology 1990 criteria for the diagnosis of FM (10) and had a disease duration of at least 1 year.…”

Section: Participantsmentioning

confidence: 99%

Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia

Harris¹,

Sundgren²,

Pang³

et al. 2008

Arthritis & Rheumatism

183

161

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Objective. Fibromyalgia (FM) is a chronic widespread pain condition that is thought to arise from augmentation of central neural activity. Glutamate (Glu) is an excitatory neurotransmitter that functions in pain-processing pathways. This study was carried out to investigate the relationship between changing levels of Glu within the insula and changes in multiple pain domains in patients with FM.Methods. Ten patients with FM underwent 2 sessions of proton magnetic resonance spectroscopy (H-MRS) and 2 sessions of functional magnetic resonance imaging (FMRI), each conducted before and after a nonpharmacologic intervention to reduce pain. During H-MRS, the anterior and posterior insular regions were examined separately using single-voxel spectroscopy. The levels of Glu and other metabolites were estimated relative to levels of creatine (Cr) (e.g., the Glu/Cr ratio). During FMRI, painful pressures were applied to the thumbnail to elicit neuronal activation. Fibromyalgia (FM) is a chronic widespread pain disorder that affects ϳ2-4% of individuals in industrialized countries (1). Although the underlying etiology of this condition is unknown, dysfunction within the central nervous system has been implicated. Results from functional magnetic resonance imaging (FMRI) (2,3), singlephoton emission tomography (4), and positron emission tomography (5) support this hypothesis.One structure that is consistently found to be associated with augmented evoked pain activity in FM is the insula (2,3). In addition to its function in speech, taste, and auditory systems, the insula is also intimately involved in somatosensory and visceral pain processing (6). It is strategically located in a bidirectional pathway between the secondary somatosensory cortex and the amygdala (6). This anatomic position may give the insula ClinicalTrials.gov identifier: NCT00142597.

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“…Clinical evidence has also shown that opioids are ineffective in suppressing pain in fibromyalgia patients (Clauw, 2014). One of the underlying mechanisms could be attributed to reduced availability of opioid receptors in the brain (Harris et al, 2007), possibly owing to excess amounts of endogenous opioids in the cerebral spinal fluid of fibromyalgia patients (Baraniuk et al, 2004). The reduced sensitivity to morphine in the ICS model may be related to functional deficits in the descending serotonergic activity (Ohara et al, 1991;Omiya et al, 2000;Nishiyori et al, 2010), which is consistent with biochemical evidence in clinical samples (Clauw, 2009).…”

Section: Discussionmentioning

confidence: 57%

Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

Mukae

Uchida

Ueda

2015

J Pharmacol Exp Ther

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Treatment of fibromyalgia is an unmet medical need. To develop novel therapies for the treatment of fibromyalgia, we explored pain therapeutic actions of existing pharmaceuticals, which inhibit the somatic symptoms frequently observed in fibromyalgia patients. This study first examined the therapeutic actions of pilocarpine, which inhibits dry-eye and dry-mouth symptoms, using an experimental fibromyalgia-like chronic pain model produced by intermittent cold stress (ICS) in mice. A single intraperitoneal and intracerebroventricular, but not intrathecal, pilocarpine administration attenuated ICS-induced thermal hyperalgesia and mechanical allodynia, and this action was abolished by muscarinic antagonist pirenzepine (i.c.v.). Treatment with 1-10 mg/kg donepezil (i.p.), which can easily penetrate into the brain, also showed similar therapeutic effects. Importantly, we found that both pilocarpine and donepezil produced antihyperalgesic effects via supraspinal action. Furthermore, repeated donepezil treatments completely cured the ICS-induced hyperalgesia and allodynia even after the cessation of drug treatments. Acute and chronic treatments of these cholinomimetics had no effects on the nociceptive threshold in control animals. By contrast, the lack of morphine (i.c.v.) analgesia initially observed in the ICS model remained in ICS model mice treated with long-term donepezil. Collectively, these findings suggest that stimulation of the muscarinic cholinergic system effectively inhibits some mechanisms underlying chronic pain in the ICS model, but does not inhibit the lack of descending pain-inhibitory mechanisms, which are driven by central morphine.

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Decreased Central μ-Opioid Receptor Availability in Fibromyalgia

Cited by 448 publications

References 43 publications

Reward responsiveness in patients with chronic pain

Reward responsiveness in patients with chronic pain

Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia

Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

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