Beyond aspirin and morphine, snail toxins for pain

Pain medications from antiquity

Many drugs used in relieving pain nowadays are based on active ingredients from plants used in traditional medicine. As early as 400 B.C., Hippocrates cited the pain-relieving effects of white willow (Salix alba) bark, whose active ingredient was isolated in the 19th century and found to be salicylic acid (originally called salicin). A chemically modified, synthetic version of salicylic acid obtained from meadowsweet (Filipendula ulmaria, formerly classified as Spiraea ulmaria) is acetylsalicylic acid which was named aspirin, giving rise to the class of analgesic (for pain), antipyretic (for fever) and anti-inflammatory drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. An opium-based elixir which was used as a potent pain reliever has been attributed to alchemists of the Byzantine era. In the 19th century, the active ingredient was isolated from opium poppy (Papaver somniferum) and found to be morphine which gave rise to the class of analgesics known as opiates.

About pain

Pain is a malady, an unpleasant sensory or emotional state that individuals can experience in their lifetime. There are various categories of pain; the two major types of chronic pain are neuropathic pain and nociceptive pain. Neuropathic pain results from damage to the nerves of the peripheral or central nervous system; it is frequently described as a burning sensation, or a pin and needle type of sensation, or that having an electrical quality, and tends to radiate in a direction that follows nerve endings. Examples are pains triggered by sciatica and diabetes. Nociceptive pain results from damage to tissues; it is often described as sharp or stabbing sensation. Examples are pains from arthritis and cardiac disease.

The continuing search for new pain medications

Because pain can affect every living person, it is not surprising that until this time, scientists and drug manufacturers are still in the search for chemical agents that can soothe pain. The aim is to develop drugs that block specific steps in the pathways of pain mechanisms while avoiding the side effects associated with NSAIDs and opiates. Aspirin and other NSAIDs are commonly used for mild to moderate pain, and are not effective against neuropathic pain. NSAIDs block the synthesis of prostaglandins which are chemicals that contribute to inflammation, but can cause gastrointestinal ulcers and stomach bleeding. Morphine and other opiates are often used for severe chronic pain, for example, cancer pain. Opiates act directly on the central nervous system, particularly by binding to the so-called opiate receptors, but can have side effects including constipation and slowdown in breathing, and can cause tolerance or addiction to the drugs.

New pain medications may be obtained from products of other living things, like the deadly toxins of snails. The conopeptides or conotoxins are peptide (small protein) toxins used by venomous marine cone snails (genus Conus) to capture their prey which may be fish, worms or other mollusks. Some conopeptides have been shown to have analgesic properties, in addition to their use as tools for neuroscientists in understanding the molecular mechanisms leading to the perception of pain.

Ziconotide, the synthetic form of the naturally occurring omega-conotoxin MVIIA which was isolated from venom of Conus magus, is already in clinical use for severe chronic pain. This peptide specifically blocks voltage-sensitive calcium channels on nerves that normally transmit pain signals. It does not induce tolerance or addiction and is 1,000 times as potent as morphine, but can cause side effects including dizziness, nausea, vomiting, confusion and severe neurological symptoms. Ziconotide is indicated only for severe chronic pain which is not remedied by other analgesics, and is administered via injection into the fluid surrounding the spinal cord with the use of an implanted microinfusion pump.

Other conopeptides which act on receptors and ion channels in the nervous system have reached clinical trials as drugs for pain. AM336 which specifically blocks calcium channel is the synthetic form of omega-conotoxin CVID, a peptide found in the venom of Conus catus. CGX-1007 is the synthetic equivalent of sleep-inducing peptide, conantokin-G, which was isolated from the venom of Conus geographus, and found to be a blocker of N-methyl-D-aspartate receptor. The synthetic form of contulakin-G, a glycopeptide (peptide with oxygen-linked carbohydrate) purified from venom of Conus geographus, is CGX-1160 which acts on neurotensin receptor. The synthetic version of alpha-conotoxin Vc1.1, a peptide found in the venom of Conus victoriae, is ACV-1 which blocks the nicotinic acetylcholine receptor. A blocker of norepinephrine transporter, Xen2174 is a synthetic derivative of chi-conotoxin MrIA, a peptide isolated from the venom of Conus marmorius.

The analgesic properties of peptide toxins from cone snails are promising. These peptides have paved the way in understanding further the detailed molecular mechanisms of pain and the connection of pain perception to the nervous system. Ultimately, they will shed light on the exact events that happen from the moment one receives a pain stimulus to the moment that one cries “Aray!”

Note: The author declares no conflict of interest with regard to this article.

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The author is a professor of Chemistry of the University of the Philippines Baguio. For nearly 15 years, she has undertaken research on the biochemistry and molecular biology of Conus peptides, and holds five US patents on these peptides. E-mail her at [email protected].