Approximately 9% of the US population suffer from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. This condition precipitates other serious pathologies 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. The origins of pain range from nociceptive (caused by tissue injury or inflammation) to neuropathic, a condition that can have many underlying causes. Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments. Migraine represents a further specific kind of pain. The pathophysiology of this condition is still not fully understood even though it is extremely common. 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.

Due to the clinical demand and the growing market for improved treatments of chronic pain, researchers have been looking for new and improved therapeutic targets. One field that is growing due to its relevance to multiple indications including pain is that of the ion channels .

In particular, sodium channels accumulate in the membranes of primary afferents around sites of injury lowering the threshold for action potential generation. This results in repetitive firing and/or evoked neural hyperexcitability, a principal feature of many chronic, in particular neuropathic, pain syndromes. Recent interest has focused on tetrodotoxin resistant sodium channels found in adult small diameter, unmyelinated, capsaicin-sensitive DRG neurons, otherwise referred to as nociceptors. The NaV1.8 channel (PN3/SNS) was the first such channel to be identified, although NaV1.9 (NaN/SNS2) has been identified more recently. Depending on the nature and degree of the injury the distribution of NaV1.8 is altered. Antisense oligonucleotide directed to NaV1.8 produces a selective and reversible block of channel protein expression in rats with spinal nerve (L5/L6) ligation and can prevent the behavioral manifestations of hyperalgesia evoked by this type of injury. Of interest this strategy had little effect on responses to non-noxious or noxious stimuli in the absence of nerve injury suggesting that this channel represents an excellent target for novel analgesics. The molecular mechanism surrounding the involvement of NaV1.8 in the etiology of pain has recently been investigated in greater detail. Following L5/L6 spinal nerve ligation NaV1.8 does not appear to contribute to neuropathic pain through an action in injured afferents because the channel is functionally downregulated in the cell bodies of injured neurons and does not redistribute to injured terminals. Although there was little change in NaV1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in NaV1.8 immunoreactivity along unmyelinated C-fiber axons within the sciatic nerve. Attenuating expression of NaV1.8 with antisense oligodeoxynucleotides prevented the redistribution of the channels and as previously described this also reversed neuropathic pain. These observations suggest that aberrant activity in uninjured C-fibers is a necessary component of pain associated with partial nerve injury. As with animals, expression of NaV1.8 is also altered in hyperalgesic humans. Similar mechanisms appear to be involved at least in patients with brachial plexus injury. Channel density was seen to decrease in sensory cell bodies of cervical dorsal root ganglia whose central axons had been injured. In contrast, density was increased in some peripheral nerve fibers just proximal to the site of injury.

Deleting the NaV1.8 channel has recently been shown to reduce visceral hyperalgesia suggesting that this channel may represent a target for conditions such as IBS and bladder hypersensitivity/urge incontinence, a common problem experienced in patients with spinal cord injury. Thus targeting the NaV1.8 channel appears to hold considerable promise for the treatment of multiple types of previously “difficult to treat” hyperalgesias.

Entry date February, 2003

Adapted from Gold et al, J Neurosci 2003 Jan 1;23(1):158-66 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk