Perispinal injection of a TNF blocker directed to the brain of rats alleviates the sensory and affective components of chronic constriction injury-induced neuropathic pain.

Neuropathic pain is chronic pain that follows nerve injury, mediated in the brain by elevated levels of the inflammatory protein tumor necrosis factor-alpha (TNF). We have shown that peripheral nerve injury increases TNF in the hippocampus/pain perception region, which regulates neuropathic pain symptoms. In this study we assessed pain sensation and perception subsequent to specific targeting of brain-TNF (via TNF antibody) administered through a novel subcutaneous perispinal route. Neuropathic pain was induced in Sprague-Dawley rats via chronic constriction injury (CCI), and thermal hyperalgesia was monitored for 10 days post-surgery. On day 8 following CCI and sensory pain behavior testing, rats were randomized to receive perispinal injection of TNF antibody or control IgG isotype antibody. Pain perception was assessed using conditioned place preference (CPP) to the analgesic, amitriptyline. CCI-rats receiving the perispinal injection of TNF antibody had significantly decreased CCI-induced thermal hyperalgesia the following day, and did not form an amitriptyline-induced CPP, whereas CCI-rats receiving perispinal IgG antibody experienced pain alleviation only in conjunction with i.p. amitriptyline and did form an amitriptyline-induced CPP. The specific targeting of brain TNF via perispinal delivery alleviates thermal hyperalgesia and positively influences the affective component of pain. PERSPECTIVE: This study presents a novel route of drug administration to target central TNF for treatment of neuropathic pain. Targeting central TNF through perispinal drug delivery could potentially be a more efficient and sustained method to treat patients with neuropathic pain.

ß-Alanine supplementation increased physical performance and improved executive function following endurance exercise in middle aged individuals.

BACKGROUND: Sarcopenia, a reduction in muscle mass and function seen in aging populations, may be countered by improving systemic carnosine stores via beta-Alanine (ß-alanine) supplementation. Increasing systemic carnosine levels may result in enhanced anti-oxidant, neuro-protective and pH buffering capabilities. This enhancement should result in improved exercise capacity and executive function. METHODS: Twelve healthy adults (average age = 60.5 ± 8.6 yrs, weight = 81.5 ± 12.6 kg) were randomized and given either 2.4 g/d of ß-alanine (BA) or Placebo (PL) for 28 days. Exercise capacity was tested via bouts on a cycle ergometer at 70% VO2 peak. Executive function was measured by Stroop Tests 5 min before exercise (T1), immediately before exercise (T2), immediately following fatigue (T3), and 5 min after fatigue (T4). Lactate measures were taken pre/post exercise. Heart rate, Rating of Perceived Exertion (RPE) and VO2 were recorded throughout exercise testing. RESULTS: PRE average time-to-exhaustion (TTE) for the PL and BA group were not significantly different (Mean ± SD; 9.4 ± 1.4mins vs 11.1 ± 2.4mins, respectively, P = 0.7). POST BA supplemented subjects cycled significantly longer than PRE (14.6 ± 3.8mins vs 11.1 ± 2.4mins, respectively, P = 0.04) while those given PL did not (8.7 ± 2.4mins vs 9.4 ± 1.4mins, respectively, P = 0.7). PL subjects were slower in completing the Stroop test POST at T4 compared to T3 (T3 = - 13.3 ± 8.6% vs T4 = 2.1 ± 8.3%, P = 0.04), while the BA group (T3 = - 9.2 ± 6.4% vs T4 = - 2.5 ± 3.5%, P = 0.5) was not. POST lactate production expressed a trend when comparing treatments, as the BA group produced 2.4 ± 2.6 mmol/L more lactate than the PL group (P = 0.06). Within group lactate production for BA (P = 0.4) and PL (P = 0.5), RPE (P = 0.9) and heart rate (P = 0.7) did not differ with supplementation. CONCLUSION: BA supplementation increased exercise capacity and eliminated endurance exercise induced declines in executive function seen after recovery. Increased POST TTE coupled with similar PRE vs POST lactate production indicates an improvement in the ability of BA to extend exercise durations. Furthermore, by countering endurance exercise's accompanying deficits in executive function, the aging population can maintain benefits from exercise with improved safety.

The imidazoline I2 receptor agonist 2-BFI attenuates hypersensitivity and spinal neuroinflammation in a rat model of neuropathic pain.

Chronic pain is a large, unmet public health problem. Recent studies have demonstrated the importance of neuroinflammation in the establishment and maintenance of chronic pain. However, pharmacotherapies that reduce neuroinflammation have not been successfully developed to treat chronic pain thus far. Several preclinical studies have established imidazoline I2 receptor (I2R) agonists as novel candidates for chronic pain therapies, and while some I2R ligands appear to modulate neuroinflammation in certain scenarios, whether they exert anti-neuroinflammatory effects in models of chronic pain is unknown. This study examined the effects of the prototypical I2R agonist 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) on hypersensitivity and neuroinflammation induced by chronic constriction injury (CCI), a neuropathic pain model in rats. In CCI rats, twice-daily treatment with 10 mg/kg 2-BFI for seven days consistently increased mechanical and thermal nociception thresholds, reduced GFAP and Iba-1 levels in the dorsal horn of the spinal cord, and reduced levels of TNF-α relative to saline treatment. These results were recapitulated in primary mouse cortical astrocyte cultures. Incubation with 2-BFI attenuated GFAP expression and supernatant TNF-α levels in LPS-stimulated cultures. These results suggest that I2R agonists such as 2-BFI may reduce neuroinflammation which may partially account for their antinociceptive effects.