A Web of a Response: Spiders toxins used to elucidate pain
A recent study published in Nature reveals the role of a voltage gated sodium ion (Nav) channel in the mechanical pain response. The study was conducted using toxins collected from the arachnid Heteroscodra maculata, the 5-inch arboreal tarantula notable for its chalky white stripes and thick rear legs. H. maculata transmits two potent toxins—Hm1a and Hm1b—to prey through its powerful bite. These toxins were found to selectively activate Nav1.1, one of many Nav channels involved in the pain response(3).
Voltage gated Na channels are channels embedded in the membrane of neurons. They play a vital role in initiating and propagating action potentials – changes in the electrical potential associated with a passage of an impulse along the membrane of a nerve cell. Their role is not restricted to the pain response but is widespread, responsible for general communication in the body (4).
The pain response is known as a multi-modal system. It is a highly complicated process involving many different neurons and receptors. Many of the Nav channels involved have already been researched such as Nav1.7, Nav1.8 and Nav1.9, where mutations in these channels have been associated with insensitivity to pain and each of these channels represent a puzzle piece in the jigsaw of nociception, the sensory nervous system’s response to certain harmful stimuli. One of the many challenges in understanding nociception, therefore, is being able to isolate each of these pieces individually so that their role in the response can be understood. A way of achieving this is by developing subtype selective drugs, usually by exploiting the properties of natural products, which then excite the sensory nociceptors such as the Nav channels to elicit pain. Osteen’s team, which published the recent study in Nature, took advantage of this approach. One of the many experiments performed by the researchers to understand the role of Nav1.1 in the mechanical pain response involved injecting Hm1a into the hind-paw of mice to interpret the immediate responses to the toxins. Some of the observations made included licking and biting the injected paw. This indicated that a nociceptive response was elicited. A similar response was seen when Hm1b was injected. When Nav1.1 channels were eliminated by deleting the coding gene, the toxin-evoked behaviours were attenuated. However, when the experiment was repeated to test heat sensitivity no change was observed. The authors concluded that Nav1.1 is hypersensitive to mechanical but not thermal stimuli.
With this understanding they further investigated whether the Nav1.1 channel was expressed by mechanically sensitive fibres of the gut, to see whether the channels were playing a role in mechanical hypersensitivity of patients with Irritable Bowel Syndrome (IBS). It was discovered that Hm1a significantly reduced the threshold for firing action potentials suggesting that Nav1.1 channels are expressed. Therefore, further research into methods of blocking these channels may provide treatments to reduce the abdominal pain in patients with IBS. On the contrary, by activating the Nav1.1 channels with the spider toxins, new strategies may be developed to tackle complex disorders, such as Alzheimer’s and autism, where partial loss of function of the channels are found(1). The study highlights the importance of natural products in elucidating complex signalling processes in higher organisms.
- http://www.thespidershop.co.uk/heteroscodra-maculata-p-2988.html#.V2STvo-cE5s (Picture)