Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Physical training is known to increase the antioxidant defence system and reduce exercise-induced oxidative stress. However, intense physical aerobic and anaerobic training and competition such as those imposed on professional rugby players, can induce an increase of oxidative stress which can be implicated with the arrival of overtraining. The aim of this study was to test the effect of training and competition load on oxidative stress, antioxidant status, haematological, and cell damage markers in high-level rugby players during a competitive season. Blood samples were collected four times in one year. Oxidative stress (Rmax), antioxidant (vitamin E, uric acid, TAC, and lag phase), haematological (neutrophils and monocytes) and biochemical (CK and myoglobin) parameters, as well as training and competition load, and competition results were measured. Intense periods of training and competition (T1 and T4) induced a significant higher maximum rate of conjugated dienes oxidation (+67.2% in T1 and +40.6% in T4) compared to those observed at the reference time (T3). Those periods also induced an increase in uric acid (+6.9% and 3.2%), and inflammatory markers such as monocytes (+13.3% and 10.7%). On the other hand, vitamin E (-8.7% in T1) and lag phase (-23.0% and -14.7%) were lower during these periods showing a possible training-induced antioxidant down-regulation. The less intense period of training (T2) was accompanied by lower neutrophils (-8.5%), CK (-53.7%), and myoglobin (-16.2%) values. The results suggest that oxidative stress and antioxidant measurement are significant in the biological follow-up of athletes.

Alpha-MSH exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western blot analysis. alpha-MSH (5 microm) reduced the nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) induced by bacterial lipopolysaccharide (LPS, 1 microg/ml) plus interferon-gamma (IFN-gamma, 50 ng/ml) in cultured astrocytes after 24 h. alpha-MSH also attenuated the stimulatory effect of LPS/IFN-gamma on prostaglandin E(2) release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the antiinflammatory effects of alpha-MSH, suggesting a MC4R-mediated mechanism in the action of this melanocortin. In astrocytes, LPS/IFN-gamma treatment reduced cell viability, increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and activated caspase-3. alpha-MSH prevented these apoptotic events, and this cytoprotective effect was abolished by HS024. LPS/IFN-gamma decreased Bcl-2, whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. Alpha-MSH produced a shift in Bax/Bcl-2 ratio toward astrocyte survival because it increased Bcl-2 expression and also prevented the effect of LPS/IFN-gamma on Bax and Bcl-2 expression. In summary, these findings suggest that alpha-MSH, through MC4R activation, attenuates LPS/IFN-gamma-induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN-gamma-induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family.

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