Correlation between CGRP Levels and the Neuropathic and Inflammatory Component of Postoperative Pain.

INTRODUCTION: In surgical procedures, tissue damage results in the release of a number of bioactive substances. Calcitonin gene-related peptide (CGRP) is a peptide released from sensory nerves, which determines its role in pain sensation. Its distribution in tissues deter-mines its role as a primary afferent neurotransmitter. AIM: To determine the effect of CGRP on postoperative pain and reactive inflammatory process after surgical removal of impacted mandibular third molars, as well as the factors that have influence upon the perception of pain. MATERIALS AND METHODS: Forty patients with bilaterally impacted mandibular third molars were included in the study. Venous blood samples were collected before and 24 hours after the surgical procedure in order to test their serum levels of CGRP and procalcitonin. Two weeks later the procedure was repeated. The difficulty of the surgical procedure, its duration and complications were assessed in all patients. RESULTS: The influence of some of the studied factors upon postoperative pain was established. Differences in the sensation of pain between the two sexes were found when comparing pain intensity reported by the patients. Significant difference between pain inten-sity after the 1st and 2nd surgical procedures (6 hours) was found in females (Z=2.63, p=0.009;), whereas in males the difference was observed at 24 hours (Z=1.99; p=0.047). Regarding the existence of sex-related association, а significant, strong positive correlation between CGRP levels after the 1st and 2nd surgical procedures (24 hours) was found in males (rxy=0.78; p=0.004), whereas in females this correlation was also significant, although moderately significant (rxy=0.44; p=0.020). CGRP levels at the first and second extractions were generally similar in males, and not as much in females. We proved significantly moderate positive association between CGRP and pulse levels measured before the second surgery (rxy=0.37, p=0.021). CONCLUSION: The results of our study suggest a significant role of CGRP in reactive (neurogenic) inflammation.

Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy.

Introduction: The determinants and mechanisms contributing to diabetic sensorimotor polyneuropathy (DSPN) remain unclear. Since neuroinflammation and altered nerve regeneration have been implicated in the pathogenesis of both DSPN and neuropathic pain, we hypothesized that the corresponding biomarkers could be associated with DSPN in general and could have the potential to discriminate between the painful and painless DSPN entities. Methods: In a cross-sectional study using multimarker proximity extension assay technology we assessed 71 serum biomarkers including cytokines, chemokines, growth factors, receptors, and others in patients with type 2 diabetes with DSPN (DSPN+) (n=304) or without DSPN (DSPN-) (n=158) and persons with normal glucose tolerance (NGT) without polyneuropathy (n=354). Results: After adjustment for multiple testing and sex, age, body mass index, HbA1c, and smoking, the serum levels of 17 biomarkers (four cytokines, five chemokines, four growth factors, two receptors, two miscellaneous) were lower in DSPN+ than in DSPN- and NGT. In DSPN+, six of these biomarkers were associated with peripheral nerve function. The concentrations of 15 other biomarkers differed between NGT and both DSPN+ and DSPN-, but not between DSPN+ and DSPN-. No differences in biomarker levels were found between patients with painful (n=164) and painless DSPN (n=140). Conclusions: Deficits in systemic cytokines, chemokines, and growth factors promoting nerve regeneration in patients with type 2 diabetes are linked to polyneuropathy in general but not specifically to the painful or painless entity. Trial registration number: NCT02243475.

Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease.

Multiple pathogenic factors may contribute to the pathophysiology of Alzheimer's disease (AD). Peripheral markers have been used to assess biochemical alterations associated with AD and mild cognitive impairment (MCI) involved in its pathophysiology. The present study was conducted to evaluate inflammatory peripheral markers in elderly patients with MCI, patients with AD and normal elderly subjects. We measured plasma levels of different cytokines (IL-6, TNF-alpha and IFN-alpha) and platelet levels of cyclooxigenase-2 (COX-2) from 34 patients with MCI, 45 patients with AD and 28 age-matched control subjects. MCI and AD patients showed similarities in TNF-alpha and COX-2 levels, and differences in IL-6 and INF-alpha. Whereas augmented IL-6 levels have been found in AD patients, a significant increase in INF-alpha has been detected only in patients with MCI possibly associated with the depression stage frequently found in cognitive impairment. In conclusion, inflammatory response may be an early factor in AD development and these changes in circulating markers are possibly related to the progression of MCI to AD.

Inhibitory effect of PACAP-38 on acute neurogenic and non-neurogenic inflammatory processes in the rat.

Inhibitory actions of pituitary adenylate cyclase activating polypeptide (PACAP) have been described on cellular/vascular inflammatory components, but there are few data concerning its role in neurogenic inflammation. In this study we measured PACAP-like immunoreactivity with radioimmunoassay in the rat plasma and showed a two-fold elevation in response to systemic stimulation of capsaicin-sensitive sensory nerves by resiniferatoxin, but not after local excitation of cutaneous afferents. Neurogenic plasma extravasation in the plantar skin induced by intraplantar capsaicin or resiniferatoxin, as well as carrageenan-induced paw edema were significantly diminished by intraperitoneal PACAP-38. In summary, these results demonstrate that PACAP is released from activated capsaicin-sensitive afferents into the systemic circulation. It diminishes acute pure neurogenic and mixed-type inflammatory reactions via inhibiting pro-inflammatory mediator release and/or by acting at post-junctional targets on the vascular endothelium.

PECAM-1, a key player in neuroinflammation.

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a 130-kDa protein, which plays a significant role in the adhesion cascade. It is therefore involved in leucocyte endothelium interaction and in leucocyte transendothelial migration during inflammation. As neuroinflammation and subsequent blood brain barrier disruption are integral processes in many neurological disorders, PECAM-1 and its soluble form (sPECAM-1) have been investigated in a number of conditions, rising hopes as a potential marker of disease activity, a possible target in treatment and a prognostic factor. It has been shown that serum and CSF levels of PECAM-1 and sPECAM-1 are increased in patients in active stages of multiple sclerosis. Similarly, they rise in individuals after ischaemic stroke. PECAM-1 has also been shown to be involved in the pathogenesis of Abeta-related cerebral vascular disorders, such as Alzheimer disease. It participates in the pathomechanism of paraneoplastic neurological disorders and in neuroinflammation in NeuroAIDS. A number of experiments on animal models were carried out in order to investigate PECAM-1 role in the above-mentioned conditions and more, including brain trauma and nerve root injury. In this review most recent investigations on PECAM-1 biology and its role in neuroinflammation have been described and discussed from a multidisciplinary point of view.

Mechanical hyperalgesia in complex regional pain syndrome: a role for TNF-alpha?

Plasma concentrations of soluble tumor necrosis factor alpha (TNF-alpha) receptor type I (sTNF-RI) were assessed in two complex regional pain syndrome (CRPS) patient groups (n = 30 and n = 16) and healthy controls (n = 25). Patients with CRPS and mechanical hyperalgesia had higher levels of sTNF-RI (1,661.8 +/- 146.8 pg/mL) compared with those with CRPS with identical clinical appearance but without hyperalgesia (1,155.9 +/- 56.3 pg/mL) and controls (1,239.5 +/- 42.9 pg/mL). This study suggests involvement of TNF-alpha in mechanical hyperalgesia of CRPS.

Dietary magnesium intake influences circulating pro-inflammatory neuropeptide levels and loss of myocardial tolerance to postischemic stress.

Severe dietary Mg restriction (Mg(9), 9% of recommended daily allowance [RDA], plasma Mg = 0.25 mM) induces a pro-inflammatory neurogenic response in rats (substance P [SP]), and the associated increases in oxidative stress in vivo and cardiac susceptibility to ischemia/reperfusion (I/R) injury were previously shown to be attenuated by SP receptor blockade and antioxidant treatment. The present study assessed if less severe dietary Mg restriction modulates the extent of both the neurogenic/oxidative responses in vivo and I/R injury in vitro. Male Sprague-Dawley rats maintained on Mg(40) (40% RDA, plasma Mg = 0.6 mM) or Mg(100) (100% RDA, plasma Mg = 0.8 mM) diets were assessed for plasma SP levels (CHEM-ELISA) during the first 3 weeks and were compared with the Mg(9) group; red blood cell (RBC) glutathione and plasma malondialdehyde levels were compared at 3 weeks in Mg(9), Mg(20) (plasma Mg = 0.4 mM), Mg(40), and Mg(100) rats; and 40-min global ischemia/30-min reperfusion hearts from 7-week-old Mg(20), Mg(40), and Mg(100) rats were compared with respect to functional recovery (cardiac work, and diastolic, systolic, and developed pressures), tissue LDH release, and free radical production (ESR spectroscopy and alpha-phenyl-N-tert butylnitrone [PBN; 3 mM] spin trapping). The Mg(40) diet induced smaller elevations in plasma SP (50% lower) compared with Mg(9), but with a nearly identical time course. RBC glutathione and plasma malondialdehyde levels revealed a direct relationship between the severity of oxidative stress and hypomagnesemia. The dominant lipid free radical species detected in all I/R groups was the alkoxyl radical (PBN/alkoxyl: alpha(H) = 1.93 G, alpha(N) = 13.63 G); however, Mg(40) and Mg(20) hearts exhibited 2.7- and 3.9-fold higher alkoxyl levels, 40% and 65% greater LDH release, and lower functional recovery (Mg(20) < Mg(40)) compared with Mg(100). Our data suggest that varying dietary Mg intake directly influences the magnitude of the neurogenic/oxidative responses in vivo and the resultant myocardial tolerance to I/R stress.

Pain mediation by prostaglandin E2 and leukotriene B4 in the human masseter muscle.

The pathophysiology behind chronic pain from masticatory muscles is unclear. Our hypothesis was that this pain is of inflammatory origin and associated with release of inflammatory mediators. The aim of this study was therefore to investigate the presence of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the masseter muscle and plasma and their relation to myalgia. Nineteen patients with fibromyalgia, 19 with local myalgia of the masseter muscle, and 11 healthy individuals were examined with regard to local muscular pain intensity at rest and pressure pain threshold. Inclusion criteria were masseter muscle pain for at least 3 months and masseter muscle tenderness on digital palpation. Samples were obtained from the masseter muscle by microdialysis, and the dialysates and venous blood samples were analyzed with regard to PGE2 and LTB4 concentration. Intramuscular levels were found in all groups, with significantly higher levels of LTB4 in the patients with fibromyalgia, in whom PGE2 was positively correlated to muscular pain. In the healthy individuals PGE2 was negatively correlated to pressure pain threshold. In both patient groups but not in the healthy individuals LTB4 increased during the consecutive samplings. PGE2 and LTB4 were detectable in the plasma of all groups. In conclusion, both PGE2 and LTB4 were found in the human masseter muscle. LTB4 levels are increased on needle trauma in patients with myalgia. PGE2 levels are related to muscular pain in patients with fibromyalgia. Masseter muscle pain therefore seems to be partly of peripheral inflammatory origin in fibromyalgia.

Tumor necrosis factor-alpha in synovial fluid and plasma from patients with chronic connective tissue disease and its relation to temporomandibular joint pain.

PURPOSE: The purpose of this study was to determine the level of tumor necrosis factor-alpha (TNF-alpha) in the temporomandibular joint (TMJ) synovial fluid (SF-TNF-alpha) and blood plasma (P-TNF-alpha) of patients with chronic inflammatory connective tissue disease and investigate its relation to TMJ pain, hyperalgesia, and allodynia. PATIENTS AND METHODS: Twenty-four patients with a diagnosis of chronic inflammatory connective tissue disease and TMJ pain were included in the study. Visual analog scale, tenderness of the TMJ, and pain at mandibular movements were registered, and the pressure pain threshold and pressure pain tolerance levels were measured. TMJ synovial fluid samples and blood plasma were analyzed for TNF-alpha and the levels related to TMJ pain, hyperalgesia, and allodynia. RESULTS: TNF-alpha was present in the TMJ synovial fluid of 8 of 24 patients at levels significantly exceeding those in plasma at the same visit. The presence of SF-TNF-alpha showed a significant positive correlation to TMJ pain at maximum voluntary mouth opening and tenderness to posterior palpation of the TMJ. CONCLUSION: Local production of TNF-alpha occurs in the TMJ synovium of patients with chronic inflammatory connective tissue disease. Pain on mandibular movement and tenderness on posterior palpation (allodynia) of the TMJ is related to the level of SF-TNF-alpha.