Approximately 9% of the US population suffers from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. This condition precipitates other serious conditions such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide. Since chronic pain is notoriously difficult to treat using currently available therapeutics, the development of analgesics has represented a major pharmaceutical objective. Some of the most common types of pain include migraine and musculoskeletal pain.

Migraine represents a recent growth area due to the development of improved treatment strategies such as the 5HT1D receptor agonist Imigran (sumatriptan), and the increased awareness and changing attitudes to the condition that this advance has brought about. Indeed, migraine is now known to affect 4-16% of the global population, representing a 60% increase over the past decade. Consequently, the antimigraine market sector has increased by five-fold to a current global value in excess of $2 billion since the mid-1990’s. Resurgent interest in migraine has led to fresh research into its pathophysiology, as well as the development of treatments with fewer side effects. As a result, new therapeutic classes such as 5-HT7 receptor antagonists are starting to emerge as candidates for the treatment of migraine.

Myofascial pain is another common painful disorder responsible for many pain clinic visits. This condition can affect any on the skeletal muscles in the body and approximately 21-93% of patients with regional pain complaints have myofascial pain.

A new neuropeptide, nociceptin/orphanin, and its receptor, ORL-1, were recently identified. The mode of action of nociceptin in pain perception is complex and both nociceptive and antinociceptive actions have been reported. In general, supraspinal nociceptin produces potent anti-analgesic actions through the blockade of central opioid action. Consequently a number of centrally acting ORL-1 receptor antagonists are in various stages of development for the treatment of chronic pain. On the other hand, the majority of functional studies have shown that spinal nociceptin produces anti-nociception through pre- and post-synaptic mechanisms. Furthermore, in a recent study, ORL-1 agonists have been shown to reduce dural vasodilatation resulting from cranial stimulation. This suggested that ORL-1 receptors located on trigeminal sensory fibers may be involved in the regulation of dural vessel diameter and that spinal ORL-1 agonists may be of use in migraine therapeutics.

Researchers based in Scandinavia have recently demonstrated that the injection of nociceptin into the temporal muscle of healthy volunteers failed to produce algesia. Likewise, when injected into tender non-dominant trapezius muscles of healthy subjects, 200pmol nociceptin also failed to affect pain levels although an acute local tenderness was reported. This suggests that although nociceptin can be used locally without increasing pain levels its use in the local treatment of myofascial pain requires further investigation. Perhaps the most interesting observation of this study is however the demonstration of numerous nociceptin-immunoreactive cell bodies in the trigeminal ganglia. This is the first time that nociceptin has been reported in the human trigeminal ganglia, which alongside earlier animal data showing that nociceptin is able to limit durovascular responses to cranial stimulation strongly supports the development of ORL-1 agonists as candidate treatments of migraine. Of interest, Zealand Pharmaceuticals are developing the nociceptin agonist ZP120 as a treatment of heart failure. In preclinical studies ZP120 produced pronociceptive effects in the tail withdrawal assay and decreased locomotor activity after icv, but not after iv administration in mice. This molecule has recently emerged successfully from a phase I study and it may be of use to investigate the effects of this molecule in models of migraine.

Entry date January, 2003

Adapted from Mork et al, Peptides 2002 Sep;23(9):1581-7 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.