Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival, and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory, or behavioral stimulation increases IGF-I input in activated regions. Entrance of serum IGF-I is triggered by diffusible messengers (i.e., ATP, arachidonic acid derivatives) released during neurovascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 (IGFBP-3). Cleavage of IGFBP-3 allows the passage of serum IGF-I into the CNS through an interaction with the endothelial transporter lipoprotein related receptor 1. Activity-dependent entrance of serum IGF-I into the CNS may help to explain disparate observations such as proneurogenic effects of epilepsy, rehabilitatory effects of neural stimulation, and modulatory effects of blood flow on brain activity.

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New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors:1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes.2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy.3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strat-227 egies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy.

Background and purpose:We previously reported that NCX 2057, a compound comprising a nitric oxide (NO)-releasing moiety and the natural antioxidant, ferulic acid (FA), inhibits pro-inflammatory mediators through NO-mediated gene regulation. Here, we have assessed the activities of NCX 2057 in models of inflammatory and neuropathic pain, and characterized its effects on cyclooxygenase (COX)-1 and COX-2. ]. NCX 2057 reversed carrageenan-induced hyperalgesic responses in mice and inhibited prostaglandin E2 formation in paw exudates. Finally, NCX 2057 competitively inhibited COX-1 and COX-2 activities in whole RAW macophages (IC50 = 14.7 Ϯ 7.4 and 21.6 Ϯ 7.5 mM, respectively). None of these properties were exhibited by equivalent treatments with FA or standard NO donor compounds. Conclusions and implications:These studies indicate that NCX 2057 is effective in chronic inflammatory and neuropathic pain models, probably because of its particular combination of anti-COX, antioxidant and NO-releasing properties.

1 The combination of classic non-steroidal antiin¯ammatory drugs (NSAIDs) with opiates induces more analgesia than the summed eect of each drug given separately. No studies have been performed using new generation NSAIDs and fentanyl nor on the duration of this eect. 2 We have studied the analgesic eect of fentanyl alone and after the administration of subeective doses of dexketoprofen trometamol in rat nociceptive responses. The responses were evoked by noxious mechanical stimulation and were recorded as single motor units in male Wistar rats anaesthetized with a-chloralose. 3 The eective dose 50 (ED 50 ) observed with fentanyl was 22.4+1.5 mg kg 71 and full recovery was apparent 20 min later. The administration of a total dose of 40 mg kg 71 of dexketoprofen trometamol did not induce any signi®cant eect on the nociceptive responses. In the presence of dexketoprofen trometamol, the ED 50 for fentanyl was 5 fold lower than before: 3.8+1.1 mg kg 71 and no signi®cant recovery was observed 45 min later. The opioid antagonist naloxone (200 mg kg 71) did not reverse the eect, although in control experiments the same dose was able to prevent any action of fentanyl given alone. 4 We conclude that the combination of fentanyl and subeective doses of dexketoprofen trometamol induces a more potent and longer lasting analgesic eect than that observed with fentanyl alone, and that this is not an opioid mediated action.

The combination of numerous classic drugs with nitric oxide donors has led to the development of new compounds with promising therapeutic activities in a great variety of situations, including cardiovascular and respiratory systems, ocular pressure, inflammation, and pain. One of the first compounds developed was NCX-701 or nitroparacetamol, resulting from the combination of paracetamol, a classic and popular analgesic used in a great number of over-the-counter medications because of its antipyretic and analgesic properties, and a nitrooxybutyroyl moiety, which releases nitric oxide at a low but steady level. Although paracetamol is devoid of most of the gastrointestinal toxicity associated with aspirin-like drugs, this type of compounds was first designed to take advantage of the cytoprotective properties of nitric oxide when released at low concentrations. However, the combination of these molecules also resulted in an unexpected enhancement of the analgesic activity of paracetamol. In fact, NCX-701 has been shown to be effective in acute nociception as well as in neuropathic pain, situations in which paracetamol and other COX inhibitors are devoid of any effect. In addition, NCX-701 is more potent and, in some circumstances, more effective than its parent compound in different models of inflammatory pain. Furthermore, whereas paracetamol lacks any effective antiinflammatory action, NCX-701 might reduce inflammation. All these results taken together imply that the mechanism of action

1 Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes inducing analgesic, anti-inflammatory and antipyretic actions. They are not devoid of severe side effects and so, the search for new compounds with similar or higher effectiveness and a lower incidence of undesired actions is important. Nitric oxide (NO)-releasing NSAIDs resulted from this search. 2 We have compared the antinociceptive effectiveness of cumulative doses of two new NO-releasing derivatives of S-ketoprofen, HCT-2037 and HCT-2040, using the recording of spinal cord nociceptive reflexes in anesthetized and awake rats and after intravenous and oral administration. ), indicating a greater activity than the parent compound. 4 In awake animals with inflammation, HCT-2037 p.o. fully inhibited mechanical allodynia, 91712% reduction, and hyperalgesia, 9478% reduction. Equivalent doses of S-ketoprofen only partially reduced either allodynia (50711%) or hyperalgesia (4074%). The effect on responses to noxious thermal stimulation was similar for the two compounds. 5 We conclude that the molecular changes made in the structure of S-ketoprofen including an NO moiety in its structure, improve the antinociceptive profile of the compound opening new perspectives in a safer use of NSAIDs as analgesic drugs.