Biology of Pain Bruce Lynn Lecture 1, PHOL G008, Fundamentals of Pain Biology of Pain Key role: PROTECTION •From external threats – sensors (nociceptors) in the skin •From internal overstresses, e.g. to the joints •Of injured tissues, by minimising use, through increased pain sensitivity (hyperalgesia) Nature of threatening stimuli? 1. Commonest - Mechanical overstressing – from external or internal source. Note, need FAST system to respond, rapid protective reflexes. 2. Heat. More than half land surface of the earth will exceed 45° for at least one month in the year. 3. Irritant chemicals • "True" irritants, external to organism, e.g. capsaicin • Agents generated in association with inflammation, e.g. bradykinin. Note, no sensing of UV or of ionising radiation. Nature of threatening stimuli? 1. Commonest - Mechanical overstressing – from external or internal source. Note, need FAST system to respond, rapid protective reflexes. 2. Heat. More than half land surface of the earth will exceed 45° for at least one month in the year. 3. Irritant chemicals • "True" irritants, external to organism, e.g. capsaicin • Agents generated in association with inflammation, e.g. bradykinin. Note, no sensing of UV or of ionising radiation. In many animals, 2 major sub-classes of nociceptor, matching 2 broad requirements: 1. Mechanical nociceptors. 2. Polymodal nociceptors (sensitive to all 3 stimuli: mech, heat, irritants). Most mammalian tissues have both types, including skin, muscles, joints, hollow visceral organs. Find same pattern even in very simple animals, e.g. Parasitic nematode, C. elegans. Play worm movie http://www.bio.unc.edu/faculty/goldstein/lab/crawl.mov Sensory cells in C. elegans. The ASH, FLP and OLQ neurones sense touch to the nose. The ASH cells in addition sense noxious chemicals and so have a polymodal response profile. AVM and ALM neurones sense light touch to the anterior region whereas PLM neurones sense light touch to the posterior region. PVD neurones sense only intense mechanical stimuli, i.e. they have a mechanical nociceptor profile. The anatomical abbreviations are L, left, R, right, D, dorsal, V, ventral. The figure shows the left lateral side of the worm. From (Kaplan & Horvitz, 1993) Relation of nociceptor activity to pain. NOT SIMPLE! ITCH. Some cutaneous stimuli, e.g. histamine, activate nociceptors but cause itch. Not understood why some nociceptor activity causes itch, some pain. Same afferents involved in both. Nociception without pain. Some tissues have nociceptors, but no pain. Notably smaller bronchioles in lung, plenty nociceptors, trigger protective (cough) reflexes, but no pain. Relation of nociceptor activity to pain. NOT SIMPLE! (continued) Pain without injury. Note IASP definition of pain: An unpleasant sensory and emotional experience associated with actual or potential tissues damage, or described in terms of tissue damage. Last phrase relates to situations where pain is reported when no injury or inflammation is present. For example, phantom limb pain; pain in certain neuropathic disorders. Clinical viewpoint on pain Famous surgeon LeRiche wrote in 1930s: “Defence reaction? Fortunate warning? But as a matter of fact, the majority of diseases, even the most serious, attack us without warning. When pain develops….it is too late…. The pain has only made more distressing and more sad a situation already long lost. In fact, pain is always a baleful gift, which reduces the subject of it, and makes him more ill than he would be without it.” LeRiche is thinking of chronic pain conditions associated with cancer, or with difficult-to-treat neuropathic diseases. In fact, there are many useful clinical pain situations, e.g. Pain from twisted ankle, stops further use and possible further damage; Angina, makes one rest and so reduces load on heart. In addition, many pain patterns are very helpful in diagnosis. But must agree with him about toothache! Pain, good or bad? Would it be better to have all tissues like the lungs? Possibly, as long as protective reflexes were effective. Where pain and protective reflexes are absent, leads to problems. For example, congenital insensitivity to pain, rare, but has high morbidity, often associated with serious joint damage due to overstress.