In addition to using glutamate as a neurotransmitter at central synapses, many primary sensory neurons release glutamate from peripheral terminals. Primary sensory neurons with cell bodies in dorsal root or trigeminal ganglia produce glutaminase, the synthetic enzyme for glutamate, and transport the enzyme in mitochondria to peripheral terminals. Vesicular glutamate transporters fill neurotransmitter vesicles with glutamate and they are shipped to peripheral terminals. Intense noxious stimuli or tissue damage causes glutamate to be released from peripheral afferent nerve terminals and augmented release occurs during acute and chronic inflammation. The site of action for glutamate can be at the autologous or nearby nerve terminals. Peripheral nerve terminals contain both ionotropic and metabotropic excitatory amino acid receptors (EAARs) and activation of these receptors can lower the activation threshold and increase the excitability of primary afferents. Antagonism of EAARs can reduce excitability of activated afferents and produce antinociception in many animal models of acute and chronic pain. Glutamate injected into human skin and muscle causes acute pain. Trauma in humans, such as arthritis, myalgia, and tendonitis, elevates glutamate levels in affected tissues. There is evidence that EAAR antagonism at peripheral sites can provide relief in some chronic pain sufferers.

Objective: To quantify polyneuropathy impairments and comorbidities utilizing the Rochester Epidemiology Project (2010 census 5 148,201).Methods: ICD-9-CM coding identified polyneuropathy cases (2006)(2007)(2008)(2009)(2010) and their 5:1 age-and sex-matched controls. Mortality and impairments were evaluated while identifying and adjusting for Charlson Index comorbidities.Results: Overall prevalence of polyneuropathy was 1.66%, and markedly rose to 6.6% in persons older than 60 years. Cases (n 5 2,892) had more comorbidities than controls (n 5 14,435) with higher median Charlson Index (6 vs 3, p , 0.001). Diabetes with end-organ disease represented the largest increased comorbidity in cases compared with controls (46.8% vs 6.5%). Diabetic polyneuropathy was the most common specific subtype (38.2%). Miscoded idiopathic cases and false-negative controls also commonly had diabetic polyneuropathy. Median modified Rankin Scale score was considerably higher for cases than controls (4 vs 1, p , 0.001). Multiple comorbidities were found associated with polyneuropathy after adjusting for diabetes co-occurrence, including pulmonary disease, dementia, and others. Polyneuropathy was an independent contributor to multiple functional impairments including difficulty walking (odds ratio [OR] 5 1.9), climbing stairs (OR 5 2.0), using an assistive device (OR 5 2.0), fall tendency (OR 5 2.4), work disability (OR 5 4.2), lower limb amputations (OR 5 3.9), and opioid use (OR 5 2.7). Prevalent cases had a younger median age at death than controls (80 vs 86 years, p , 0.001), and incident cases had a 6-month shorter survival. Conclusions:Polyneuropathies have notable neurologic impairments beyond their identified multiple comorbidities. Life expectancy is shortened. Diabetic polyneuropathy is underidentified. The quantified extent of the disease burden and refined comorbidity associations emphasize that greater research efforts and health care initiatives are needed. Neurology ® 2015;84:1644-1651 GLOSSARY ADL 5 activities of daily living; CI 5 confidence interval; CPT 5 current procedural terminology; ICD-9-CM 5 International Classification of Diseases, Ninth Revision, Clinical Modification; IQR 5 interquartile range; mRS 5 modified Rankin Scale; OR 5 odds ratio; REP 5 Rochester Epidemiology Project.

OBJECTIVE To assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side-effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival. METHODS Olmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments, and ICD-9 diagnostic codes for all subjects. RESULTS A total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. 5-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06–3.69). CONCLUSIONS Results from our population-based study are consistent with previous reports of high incidence of CIPN in the first two years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study of among survivors.

IMPORTANCE Polyneuropathy is one of the most common painful conditions managed within general and specialty clinics. Neuropathic pain frequently leads to decisions about using long-term opioid therapy. Understanding the association of long-term opioid use with functional status, adverse outcomes, and mortality among patients with polyneuropathy could influence disease-specific decisions about opioid treatment.OBJECTIVES To quantify the prevalence of long-term opioid use among patients with polyneuropathy and to assess the association of long-term opioid use with functional status, adverse outcomes, and mortality. DESIGN, SETTING, AND PARTICIPANTSA retrospective population-based cohort study was conducted of prescriptions given to patients with polyneuropathy and to controls in ambulatory practice between January 1, 2006, and December 31, 2010, to determine exposure to long-term opioid use as well as other outcomes. The latest follow-up was conducted through November 25, 2016.EXPOSURES Long-term opioid therapy, defined by 1 or multiple consecutive opioid prescriptions resulting in 90 continuous days or more of opioid use. MAIN OUTCOMES AND MEASURESPrevalence of long-term opioid therapy among patients with polyneuropathy and controls. Patient-reported functional status, documented adverse outcomes, and mortality were compared between patients with polyneuropathy receiving long-term opioid therapy (Ն90 days) and patients with polyneuropathy receiving shorter durations of opioid therapy. RESULTS Among the 2892 patients with polyneuropathy (1364 women and 1528 men; mean [SD] age, 67.5 [16.6] years) and the 14 435 controls (6827 women and 7608 men; mean [SD] age, 67.5 [16.5] years), patients with polyneuropathy received long-term opioids more often than did controls (545 [18.8%] vs 780 [5.4%]). Patients with polyneuropathy who were receiving long-term opioids had multiple functional status markers that were modestly poorer even after adjusting for medical comorbidity, including increased reliance on gait aids (adjusted odds ratio, 1.9; 95% CI, 1.4-2.6); no functional status markers were improved by long-term use of opioids. Adverse outcomes were more common among patients with polyneuropathy receiving long-term opioids, including depression (adjusted hazard ratio, 1.53; 95% CI, 1.29-1.82), opioid dependence (adjusted hazard ratio, 2.85; 95% CI, 1.54-5.47), and opioid overdose (adjusted hazard ratio, 5.12; 95% CI, 1.63-19.62). CONCLUSIONS AND RELEVANCEPolyneuropathy increased the likelihood of long-term opioid therapy. Chronic pain itself cannot be ruled out as a source of worsened functional status among patients receiving long-term opioid therapy. However, long-term opioid therapy did not improve functional status but rather was associated with a higher risk of subsequent opioid dependency and overdose.

Most, if not all, dorsal root ganglion (DRG) neurons use the neurotransmitter glutamate. There are, however, conflicting reports of the percentages of DRG neurons that express glutaminase (GLS), the enzyme that synthesizes glutamate, ranging from 30% to 100% of DRG neurons. Defining DRG neuron populations by the expression of proteins like GLS, which indicates function, is routinely accomplished with immunolabeling techniques. Proper characterization of DRG neuron populations relies on accurate detection of such antigens. It is known intuitively that fixation can alter immunoreactivity (IR). In this study, we compared the effects of five formaldehyde concentrations between 0.25% and 4.0% (w/v) and five picric acid concentrations between 0.0% and 0.8% (w/v) on the IR of GLS, the voltage-gated sodium channel 1.8 (Nav 1.8), and the capsaicin receptor TRPV1. We also compared the effects of five incubation time lengths from 2 to 192 hr, in primary anti-serum on IR. Lowering formaldehyde concentration elevated IR for all three antigens, while raising picric acid concentration increased Nav 1.8 and TRPV1 IR. Increasing IR improved detection sensitivity, which led to higher percentages of labeled DRG neurons. By selecting fixation conditions that optimized IR, we found that all DRG neurons express GLS, 69% of neurons express Nav 1.8, and 77% of neurons express TRPV1, indicating that some previous studies may have underestimated the percentages of DRG neurons expressing these proteins. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.