Chili peppers and pain

1. Chili peppers and pain

2. 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

3. 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

4. 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 mostwidely cultivated • sweet bell peppers ---> hot peppers • Capsicum frutescens mainly in the tropics - more fiery taste such as tabasco pepper

5. 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

6. 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

7. 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

8. 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)

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. Ergot and migraine

22. 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

23. 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

24. 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)

25. 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

26. 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 inflammationoccurs is unknown

27. 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

28. 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

29. Ergot alkaloids Vindoline Vinblastine (Catharanthus)

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. Ergotamine • Produced by the ergot (sclerotium) of Clavicepspurpurea • Fungal disease of rye and other grasses

37. 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)

38. 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

39. Claviceps purpurea Ergot of rye

40. 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

41. 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

42. 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