Chili peppers and pain

Capsicum peppers Discovered by Columbus and introduced to Spain Capsicum fruits as pungent as the Oriental black pepper He believed that his voyage west in search of spices had been justified

Early history of Capsicum peppers Cultivated for thousands of years in tropical America Exact time of domestication not known Fragments of a 9000 year old chili pepper were discovered in a Mexican cave After their introduction to Spain, spread throughout Europe, Asia, and Africa

Botany Fruits of genus Capsicum, several cultivated species and hundreds of varieties Member of Solanaceae (nightshade family) Fruits are berries - immature fruits green and mature fruits vary from yellow to purple to red, from long narrow to spherical Capsicum annuum most widely cultivated sweet bell peppers ---> hot peppers Capsicum frutescens mainly in the tropics - more fiery taste such as tabasco pepper

Capsaicin Biting taste due to the alkaloid capsaicin Found in the seeds and placental area Capsaicin content is negligible in the sweet bell peppers and high concentrations in hot chili, jalapeno, or habanero peppers Capsaicin can be tasted in concentrations as low as one part per million

Traditional medical uses In Andean cultures, chili peppers were used against severe headaches and strokes Aztecs, Mayans, and Incas used chili peppers to suppress the desire for alcohol, to treat poor memory, and to serve as an aphrodisiac Ground chili peppers, added to milk, were applied externally to reduce swellings

Contemporary uses of capsaicin Utilized as a pepper spray Used in creams for localized pain relief Application 2 to 4 times/day for 2 to 4 weeks will provide pain relief Continuous application needed

Use of capsaicin creams & gels Capsaicin-containing topical creams and ointments are available as over-the-counter products to ease joint and muscle pains Also for relieving pain from shingles -post-herpes zoster condition (caused by reactivation in adults of the chicken pox virus experienced in childhood)

Capsaicin Receptors Capsaicin causes burning when ingested or when applied to skin Recent study located capsaicin receptor on neurons Same receptor that senses heat but not all types of pain

Receptors Capsaicin and structurally related molecules bind to specific vanilloid receptors (VR1) located on the sensitive peripheral terminals of nociceptors Receptor activation triggers Ca+ influx into the neurons and firing of action potentials Apparently releasing Substance P

Substance P Main neurotransmitter for relaying pain signals to the brain Also implicated in a number of diseases including arthritis, psoriasis, and inflammatory bowel disease When eating chili peppers capsaicin produces the sensation of heat caused by the irritation of the trigeminal cells that release substance P

Topical capsaicin Capsaicin, applied to the skin, can disrupt this process Causes sensory nerve fibers to deplete substance P, and prevents them from renewing their diminished supply With fewer neurotransmitters available, neurons are unable to transmit pain signals effectively, and the individual feels less pain

Other ideas Repeated or lengthy application inactivates the receptive terminals of nociceptors, and they may degenerate Also may desensitizing nerves to the VR1 signal As a result capsaicin itself can be used as an analgesic in cases in which the pain is maintained by anatomically intact sensitized primary nociceptors

Not permanent cure Process is reversible. After capsaicin-containing cream or ointment is no longer applied topically, more substance P may be produced Pain may return

VR1 Receptors The work is among the first to identify a molecular basis for a pain response By blocking VR1, researchers might be able to find more effective treatments for chronic pain due to arthritis, spinal cord injury or nerve damage caused by diabetes Find better ways was to block VR1 receptors

Efficacy of capsaicin Review of 13 clinical trials - 991 patients - dble blind study 480 subjects, 511 controls Topically applied capsaicin is useful in alleviating the pain associated with diabetic neuropathy, osteoarthritis, and psoriasis Studied not completely blinded

Disadvantages of capsaicin In the first days of its application, it commonly produces intolerable burning, so that many patients discontinue their use In many patients pain relief is unsatisfactory Concentration of capsaicin in commercially available preparations may be too low Anecdotal evidence that application of capsaicin (>5%) can produce lengthy pain relief in some patients with neuropathic pain

VR1 Receptors VR1 expressed by neurons throughout nervous system Endogenous compounds must bind there - vanilloids VR1 also in the brain Endogenous vanilloids have been suggested to be involved in control of emotions and learning

VR1 in brain The recent finding of vanilloid receptors in several brain areas suggests that other therapeutic uses may eventually appear However, the wide distribution of these receptors also suggests that these drugs might cause a broad range of side-effects

Ergot and migraine

Migraine Headaches Migraine headaches affect 28 million Americans, 75 % of whom are women Migraines can cause significant disability Costs about $13 billion in missed work or reduced productivity annually in US

Migraines Migraines usually begin between the ages of 5 and 35 Peak prevalence is between the ages of 35 and 45 Some people can get as many as 10 migraines a month, but the average is around 1.5 per month

Migraine symptoms Include pain, extreme sensitivity to light and sound, nausea and vomiting The pain is an intense pulsing or throbbing pain usually on one side of the head - during 4 to 72 hrs Some individuals (15% to 20%) can predict the onset of a migraine with tell-tale signs that include visual disturbances (aura)

Cause of migraines For many years, scientists believed that migraines were linked to the dilation and constriction of blood vessels in the head Now believe that cause is inherited abnormalities in certain cells in the migraine pain center located in the brainstem As neurons fire, surrounding blood vessels dilate and become inflamed, causing the characteristic pain of a migraine

Other ideas Recent study found that the meninges, (membranes surrounding the brain) are inflamed during a migraine attack Some believe this is the source of migraine pain although they acknowledge that blood flow changes do occur Exactly how this inflammation occurs is unknown

What triggers migraine? Lack of food or sleep Exposure to light Hormonal irregularities in women Anxiety, stress or relaxation after stress, and fatigue also triggers

Treatment Several different treatments but ergot alkaloids dihydroergotamine and ergotamine frequently drugs of choice Used to treat severe, throbbing headaches, such as migraine and cluster headaches Will not relieve any kind of pain other than throbbing headaches

Ergot alkaloids Vindoline Vinblastine (Catharanthus)

Ergotamine and Dihydroergotamine Cause blood vessels in the body to constrict Can lead to serious side effects that are caused by a decrease in the flow of blood to many parts of the body Because of this, they are usually used for patients whose headaches are not relieved by acetaminophen, aspirin, or other pain relievers

Drugs are often mixtures The caffeine present in many ergotamine-containing combinations helps ergotamine work better and faster by causing more of it to be quickly absorbed into the body Belladonna alkaloids in some combinations help to relieve nausea and vomiting, which often occur together with the headaches and also help the patient relax and even sleep

Administration Migraine drugs often taken on a regular basis to prevent attacks Other sufferers only take medication during attack New nasal ergotamine sprays allow for quicker absorption

Mode of action Alkaloids are vasoconstrictors that are believed stimulating 5-HT1B and 5-HT1D receptors 5-HT1B receptors are located on the vascular smooth muscle cells, and their stimulation causes vasoconstriction 5-HT1D receptors are located on the endings of the primary nociceptive nerve fibers in the peripheral and central nervous system

5-HT1D receptors In peripheral nervous system nociceptive nerve endings coil around the cranial blood vessels and are activated when the blood vessels dilate Stimulation of the 5-HT1D receptors inhibits the release of chemicals that cause pain and inflammation, such as substance P and others

5-HT receptors Ergotamine and similar drugs affect migraine two ways - they induce vasoconstriction and inhibit neurogenic inflammation In addition in the CNS, stimulation of 5-HT1D receptors results in inhibition of pain transmission, another mode of action that may be involved in the abortive treatment of migraine

Ergotamine Produced by the ergot (sclerotium) of Claviceps purpurea Fungal disease of rye and other grasses

Claviceps purpurea Cause of ergot or rye Ascospores are produced in the spring at about the same time rye is flowering Ascospores land on flower, invades the ovary and destroys it - produces conidia in a sticky, sweet material that attracts insects - spread spores to other flowers As season progresses, mycelium in ovary develops into a hard, dark structure called an ergot (technically it is a sclerotium - hardened fungal tissue)

Ergot Overwinters Ergot replaces the grain - it may be harvested along with the grain or it may fall to the ground and overwinter In the spring, the ergot produces several stroma each containing perithecia Ascospores are long and thin and start the infection cycle all over when they are released from the perithecia

Claviceps purpurea Ergot of rye

Ergotism Ergot contains a number of toxic alkaloids, if harvested with the grain and milled into the flower - it can cause a disease called ergotism During Middle Ages called “Dancing Mania” and “St. Anthony’s Fire” Ergotism can also occur in grazing animals that forage on contaminated grain Many different alkaloids --- cause many different effects

Alkaloids in Ergot Some of the ergots constrict blood vessels and impair circulation - in extreme conditions can result in gangrene - limbs may drop off or require amputation Other toxins affect the CNS resulting in hallucinations and convulsions - loss of mental function Feelings of burning in calves or intense cold

Alkaloids in ergot With modern milling techniques, ergotism rare Outbreak in France in 1951 - 4 deaths and 150 hospitalized 1977 in Ethiopia on contaminated barley Salem Witches – may have been ergotism Many alkaloids present - several others besides ergotamine