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 most widely 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 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 inflammation occurs 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 Claviceps purpurea
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 deaths and 150 hospitalized
1977 in Ethiopia on contaminated barley
Salem Witches – may have been ergotism
Many alkaloids present - several others besides ergotamine