F 13640, a novel candidate analgesic

It has been estimated that 9% of the US population suffers from moderate to severe non-cancer-related pain. Acute pain resulting from conditions such as headache, muscle spasms, dental problems or following surgery, affects 90 million Americans every year. Chronic pain is more troubling as it sparks a viscous cycle of clinical problems and often precipitates depression and/or life-style changes. Furthermore, establishing prolonged analgesia, free of serious side effects is a particularly challenging area of medicine. Estimates of the number of Americans suffering chronic pain range from 40-70 million. The total economic cost of pain is $100 (US) billion in the US alone and the estimated worldwide market for pain and inflammation treatments has been estimated as $18.7 (US) billion. It is therefore not surprising that the development of analgesics has represented a major pharmaceutical objective. (click here for "Pain 2002" an analysis of future directions in analgesic therapeutics).

In a recent DiscoveryDossier we describe the therapeutic potential of 5-HT7 receptor antagonists in the unmet field of migraine prophylaxis (click here for further details). 5-HT7 receptors are similar pharmacologically to 5-HT1A receptors that have also been reported to mediate pain and hyperalgesia in peripheral sensory neurons via direct activation of C-type fibers.

Researchers from Pierre Fabre have, in a recent series of studies, investigated the analgesic effects of 5-HT1A receptor activation by the very-high-efficacy, selective 5-HT1A receptor agonist F 13640. This molecule was discovered to produce broad-spectrum analgesia via a central mechanism of action. Remarkably, and in direct contrast to morphine, Bruins Slot et al (2003) have shown that analgesia grows rather than decays with chronicity (ie inverse tolerance). Furthermore, the efficacy of analgesia produced by F 13640 appears to be most effective in animals with experimental pain of high intensity and prolonged duration thereby targeting conditions that are in greatest need of improved analgesics. Finally, these effects can be dissociated from the 5-HT syndrome that precludes the usefulness of many 5-HT1A receptor agonists due to associated alterations in cognition, behavior, autonomic nervous system function, and neuromuscular activity.

More recently, Jaroslava Buritova and colleagues examined the mechanism by which F 13640 produces inverse tolerance. The hypothesis tested was that morphine initially produces analgesia that is superceded by hyperalgesia; F 13640 on the other hand is proposed to initially produce the opposite effects. Indeed initial analgesia has already been demonstrated in control animals (but not hyperalgesic animals) following acute administration. Tolerance and inverse tolerance have been proposed to result from a shift in baseline activity within pain pathways and Dr Buritova’s group has investigated this by determining c-fos levels within the spinal cord. While little expression was measured under control conditions, acute activation of 5-HT1A receptors with F 13640 increased c-fos levels in neuronal populations (in particular, dorsal horn laminae I–II and V–VI) that are involved in spinal cord nociceptive signal transmission. This data supports the concept that F 13640 modulates central pain pathways and further studies investigating its effect on the activity of these pathways following chronic administration and or in the context of chronic pain are eagerly awaited.

Entry date Wednesday, July 02, 2003

Adapted from Buritoiva et al, Eur J Pain. 2003;7(3):241-9

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