The mechanisms and management of persistent postsurgical pain.

An estimated 10%-50% of patients undergoing a surgical intervention will develop persistent postsurgical pain (PPP) lasting more than 3 months despite adequate acute pain management and the availability of minimally invasive procedures. The link between early and late pain outcomes for surgical procedures remains unclear-some patients improve while others develop persistent pain. The elective nature of a surgical procedure offers a unique opportunity for prophylactic or early intervention to prevent the development of PPP and improve our understanding of its associated risk factors, such as pre-operative anxiety and the duration of severe acute postoperative pain. Current perioperative pain management strategies often include opioids, but long-term consumption can lead to tolerance, addiction, opioid-induced hyperalgesia, and death. Pre-clinical models provide the opportunity to dissect mechanisms underpinning the transition from acute to chronic, or persistent, postsurgical pain. This review highlights putative mechanisms of PPP, including sensitisation of peripheral sensory neurons, neuroplasticity in the central nervous system and nociceptive signalling along the neuro-immune axis.

Gate control of sensory neurotransmission in peripheral ganglia by proprioceptive sensory neurons.

Melzak and Wall's gate control theory proposed that innocuous input into the dorsal horn of the spinal cord represses pain-inducing nociceptive input. Here we show that input from proprioceptive parvalbumin-expressing sensory neurons tonically represses nociceptor activation within dorsal root ganglia. Deletion of parvalbumin-positive sensory neurons leads to enhanced nociceptor activity measured with GCaMP3, increased input into wide dynamic range neurons of the spinal cord and increased acute and spontaneous pain behaviour, as well as potentiated innocuous sensation. Parvalbumin-positive sensory neurons express the enzymes and transporters necessary to produce vesicular GABA that is known to be released from depolarized somata. These observations support the view that gate control mechanisms occur peripherally within dorsal root ganglia.

Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia.

Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil-derived mediators and peripheral nerve sensitization is already established. Our observations suggest approaches for targeting fibromyalgia pain via mechanisms that cause altered neutrophil activity and interactions with sensory neurons.

Inhibition of somatosensory mechanotransduction by annexin A6.

Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron-derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6-deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cation channel Piezo2, which mediates a rapidly adapting mechano-gated current linked to proprioception and touch, and a decrease in mechanically activated, slowly adapting currents. Conversely, overexpression of annexin A6 in sensory neurons inhibited rapidly adapting currents that were partially mediated by Piezo2. Furthermore, overexpression of annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis, a disease in which mechanically evoked pain is particularly problematic. These data suggest that annexin A6 can be exploited to inhibit chronic mechanical pain.

All-cause and cardiovascular mortality in middle-aged people with type 2 diabetes compared with people without diabetes in a large U.K. primary care database.

OBJECTIVE: Middle-aged people with diabetes have been reported to have significantly higher risks of cardiovascular events than people without diabetes. However, recent falls in cardiovascular disease rates and more active management of risk factors may have abolished the increased risk. We aimed to provide an up-to-date assessment of the relative risks associated with type 2 diabetes of all-cause and cardiovascular mortality in middle-aged people in the U.K. RESEARCH DESIGN AND METHODS: Using data from the General Practice Research Database, from 2004 to 2010, we conducted a cohort study of 87,098 people, 40-65 years of age at baseline, comparing 21,798 with type 2 diabetes and 65,300 without diabetes, matched on age, sex, and general practice. We produced hazard ratios (HRs) for mortality and compared rates of blood pressure testing, cholesterol monitoring, and use of aspirin, statins, and antihypertensive drugs. RESULTS People with type 2 diabetes, compared with people without diabetes, had a twofold increased risk of all-cause mortality (HR 2.07 [95% CI 1.95-2.20], adjusted for smoking) and a threefold increased risk of cardiovascular mortality (3.25 [2.87-3.68], adjusted for smoking). Women had a higher relative risk than men, and people <55 years of age had a higher relative risk than those >55 years of age. Monitoring and medication rates were higher in those with diabetes (all P < 0.001). CONCLUSIONS: Despite efforts to manage risk factors, administer effective treatments, and develop new therapies, middle-aged people with type 2 diabetes remain at significantly increased risk of death.