The document defines pain and classifies its types. It discusses pain sensation and its significance as a protective mechanism. Pain is classified as nociceptive, neuropathic, or psychogenic, and can be acute or chronic. The document also describes pain receptors, their distribution, stimulation, and the various reactions caused by pain, including motor, autonomic, emotional, and hyperalgesia.

1. بسم الله الرحمن الرحيم

3. PAIN SENSATION According to The International Association for the Study of Pain (IASP): Definition: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. 1) warning signal against tissue damage . Pain is one of the most prominent symptoms of tissue damage. 2) Initiate protective reflexes which causes the subject to get rid of the painful stimulus, or at least, to minimize tissue injury or damage Significance

5. If persistent, physiological pain may progress to a pathological condition itself, often referred to as maladaptive pain, in which case pain is dissociated from the original noxious stimulation or the healing process and thus does not represent anymore a symptom of disease but rather abnormal sensory processing due to damage to tissues (inflammatory pain) or the nervous system (neuropathic pain), or to abnormal function of the nervous system itself (functional pain) . pain resulting from activation of pain receptors may be referred to as adaptive or physiological pain, because it minimizes tissue damage and promotes healing.

6. Pain is classified into nociceptive , neuropathic and psychogenic ; all can be either acute or chronic. Pain is defined as chronic if persists more than 7 weeks. 1. Nociceptive is pain caused by tissue damage (inflammation) which stimulate pain receptors (nociceptors). 2. Neuropathic: (pain due to injury of nerve pathway) site of injury: Central Central pain (thalamic infarct). Mixed Plexus avulsion, Post herpetic neuralgia. Peripheral Neuroma, nerve compression, phantom, neuralgias. character: burning, tingling, numbness, pressing, squeezing, itching, constant +/- intermittent shooting, lancinating, electric. 3. Psychogenic: (difficult to differentiate whether secondary to or actual cause of pain), anxiety, depression (30% of depressives complain of pain on initial presentation). Classification:

7. Types of Pain Receptors Free nerve endings which are morphologically similar but functionally specific . They are classified according to their sensitivity into: Polymodal Pain Receptors (most pain receptors) These respond to a combination of mechanical, thermal, and chemical noxious stimuli. Mechanical Pain Receptors respond to strong mechanical forces, such as cutting, crushing, pricking, or even firm pressure on tissues. Thermal Pain Receptors respond to excessive changes in temperature (above 45 o C and below 10 o C). Chemical Pain Receptors respond to noxious chemical stimuli. Pain Receptors (Nociceptors)

8. Distribution of Pain Receptors Pain receptors are found in most tissues of the body but varies in their density. They are abundant and widely spread in the skin and some internal tissues such as: - the periosteum of the bone, - arterial walls, - joint surfaces, - the dura of the falx and tentorium in the cranial cavity, - the skeletal muscle, - the parietal layer of serous membranes.

9. Many of the other deep tissues and viscera are poorly supplied with pain receptors. So, - for pain to occur, painful stimulus must by intense and widespread. - The deep & visceral pain are poorly localized. On the other hand, the brain itself and also the parenchymal tissues of the liver , kidneys , and lungs have no pain receptors. They are called “pain insensitive structures” N.B.: Serious diseases in these structures don’t produce pain till they extend to a pin sensitive structure like arterial wall or serous covering.

10. Pain Threshold: Pain threshold is the lowest intensity of stimulus that can cause pain when the stimulus is applied for sufficient period of time. Pain threshold can be measured in many ways. One of the accurate methods to quantify the threshold is heating the skin with measured amounts of radiant heat from a calibrated electric lamp. It has been shown that the majority of subjects begin to perceive pain when the skin temperature reaches 45 o C, and almost everyone perceives pain before the temperature reaches 47oC. So, it seems that the great majority of people do not show significant differences in their sensitivity to painful stimuli. However, they differ widely in their reaction to pain.

11. Stimulation of Pain Receptors: noxious stimuli are strong enough -----> tissue damage ------> release of chemical agents from destructed cells into the surrounding interstitial spaces which are called “pain producing compounds” (PPCs) ------> stimulate pain receptors in the affected tissues. PGE 2 IL-1 Both  threshold of pain receptors facilitating their stimulation

12. The PPCs may be classified into: 1- Direct stimulators Substances which when reach specific threshold directly stimulate pain receptors ----> pain, as: - K + ions. - H + ions - Serotonin. - Histamine - Bradykinin 2- Sensitizers Substances which lower the threshold for stimulation of pain receptors by direct stimulators ----> facilitate pain production. They include: a) Substances released by the injured tissues as: PGE2 & IL-1 b) Substances released by pain receptors through antidromic impulses as: substance P N.B.: Substance P also stimulate mast cells to release histamine which is a direct stimulator.

13. The surface membrane of pain receptors contain several molecular receptors which can be activated by various PPCs. Function Molecular receptor Stimulation Acid sensing receptor (H+) Stimulation Purinergic receptor (ATP) Stimulation Transient receptor potential rec. (thermal) Stimulation & sensitization Bradykinin receptor Stimulation & sensitization Histamine recptor Stimulation & sensitization Serotonin receptor sensitization Prostaglandin receptor sensitization Interleukin-1 receptor sensitization Substance P receptor Inhibition Cannabinoid receptor Inhibition Opioid receptor

15. Pain Tolerance: It is the maximum intensity of pain can be tolerated by the subject without obvious complaint. Pain tolerance is affected by a number of factors: - Anxiety, depression & fatigue ------>  pain tolerance. - rest, sever exercise & strong emotional excitement ------>  pain tolerance. Non Adaptation of Pain Receptors Pain receptors do not adapt to continuing noxious stimuli. Non adaptation to pain serves a protective function to keep the individual trying to remove the damaging stimulus or to get away from it.

16. THE CHARACTER (QUALITY) of pain 1) Pricking or Cutting Pain 2) Burning Pain 3) Aching Pain 4) Throbbing Pain 5) Colicky Pain A sharp and localized pain. It is of cutaneous origin and is caused by pricking or cutting the skin by a sharp object. A less well localized pain. It is usually of cutaneous origin and is caused by burns or inflammations of the skin . A dull-aching nature. It is more diffuse and felt coming from deeper tissues, e.g. rheumatic pains. is characterized by fluctuation of its intensity with arterial pulsations. It results from localized inflammation in deep tissues, as in abscess formation. Pain results from spasm of plain muscles in the walls of hollow viscera.

17. Visceral Somatic sympathetically innervated organs can be transferred to body surface cutaneous, deep tissues site vague distribution and Quality deep, ache, dragging, squeezing acute: colic, paroxysmal, +/- N/V, sweating, BP and heart rate changes constant, localised aching, throbbing, gnawing character Acute nociceptive pain:

18. Slow (delayed) pathophysiological pain Fast (Immediate) physiological pain Shortly after application if tissue damage occurs Longer duration Burning Poorly-localized C-fibers Thalamus Substance-P * Associated with arousal, autonomic & emotional reactions Abolished by local anaethesia & morphine onset: during application of the stimulus Duration: short duration. Nature: pricking Localization: well-localized Afferent: A-delta fibers Higher center: CC Neurotransmitter: glutamate Significance: * determine site & severity. * Initiate withdrawal reflexes. Abolished by deep pressure and not abolished by morphine.

19. Reactions to Pain: 1) Somatic Motor Reactions 2) Autonomic Reactions 3) Emotional and Psychogenic Reactions 4) Hyperalgesia.

20. 1) Somatic Motor Reactions a) Excess neuromuscular excitability throughout the body. b) Withdrawal Reflexes. - initiated by cutaneous pain . - Aim to withdraw the whole body or a part of it away from a painful stimulus mainly by contraction of flexor muscles. - It is a prepotent reflex; inhibit all other reflexes during its occurrence. Reflex spasm of the nearby skeletal muscles in case of deep pain ----> minimize mobilization of the pained part ----->  stimulation of pain receptors. c) Immobilization Reaction. d) Guarding Reaction. Reflex spasm of the overlying skeletal muscles in case of visceral pain ---->  stimulation of pain receptors in the diseased viscus.

21. 2) Autonomic Reactions Mild Cutaneous pain ------> a pressor reaction = rise of blood pressure and heart rate , mediated by sympathetic stimulation . Sever cutaneous, deep and visceral pain ------> a depressor reaction associated with hypotension , bradycardia , and nausea , due to parasympathetic stimulation . Such pain is often described as sickening pain and may be accompanied by vomiting.

22. 3) Emotional and Psychogenic Reactions Anxiety , fear , crying , depression , as well as the feeling of being hurt may be felt by the pained person. these reactions vary: - From person to person on exposure to similar pain stimuli . - in the same person according to his emotional state : - Worry about the cause of pain augment the feeling of pain . Thus, Patients suffer than healthy subject to the same degree of pain. - Strong emotional excitement & sever physical exertion may block the feeling of pain. Thus, seriously wounded soldiers in a battlefield suffer little or no pain till the battle is over.

23. NEURAL PATHWAYS FOR PAIN Pain impulses are transmitted to CNS by two separate pathways, which correspond to the two different types of pain; a fast-acute (pricking) pain , and a slow-chronic (burning or aching) pain.

29. Cutaneous Hyperalgesia Definition: Increased skin sensitivity to pain. Types: 1- Primary hyperalgesia. 2- Secondary hyperalgesia. 2- Secondary hyperalgesia 1- Primary hyperalgesia - Develops later. - Shorter duration than 1ry. - In healthy skin surrounding red area. - Pain is felt more sever than normal. Central sensitization explained by convergence-facilitation theory. - Develop 30-60 min. after injury. - Lasts for several hours or days. - In the area of redness. - Non-painful stimuli (as touch) becomes painful. Mechanism: Decreased pain threshold due to local axon reflex releasing substance P

30. Referred Pain Definition: Pain felt away from the original site of the painful stimulus. Radiating pain: Pain which appear to migrate away from its original site. Referred pain is a part of radiating pain. Visceral pain is usually referred. Deep pain may be referred. Cutaneous pain is never referred. Site of referral is determined by dermatomal rule : The pain from a viscera is referred to a somatic structure (skin or deep structure) which were developed in the same embryonic segment and supplied by the same dorsal root ganglia. Abnormal sites are due to migration of viscera.

32. Mechanism of referred pain (Convergence-projection theory): Nerves from viscera and from a somatic structure developed in the same embryonic segment develops from the same DRG and converge to a great extent on the same SGR. Thus, visceral pain afferents usually excite the same spinothalamic tract neurons and the same neurons in the higher centers that are activated by the pain afferents from somatic structures to which the visceral pain is referred. Brain is accustomed to receive pain impulses from somatic structures as the frequency of somatic pain is much more frequent than the visceral pain. Thus, the brain would misinterpret the origin of the visceral pain impulses, and the pain is perceived as if arising from the skin area or deep somatic structures which are innervated by the same spinal segments that innervate the diseased viscera.

34. Examples of Referred Pain from Visceral Organs Cardiac Pain is referred mainly to the base of the neck , over the left shoulder , inner side of the left arm , and under the sternum (retrosternal). All these structure developed from embryonic segments which enter the spinal coed along 2,3,4,5 thorathic nerves. 2. Gall Bladder Pain is referred to epigastric region , slightly to the right, and if an inflammed gall bladder irritates the diaphragm, the pain may also be referred to the tip of the right shoulder & small area at the tip of the right scapula . 3. Renal and Ureteric Pain is usually felt directly behind the diseased viscera in the back. However, the pain is occasionally referred to the anterior abdominal wall near the inguinal region, scrotum & testis (L1).

35. 4. Appendicitis Pain is initially referred to a remote area around the umbilicus (Th10), but when the inflammatory process spreads to the overlying parietal peritoneum the pain is also localized in the right iliac fossa just over the site of irritation. 5. Gastric Pain is usually referred to the skin of epigastric region in the anterior abdominal wall between the xyphoid process and the umbilicus .

36. Relief of pain (analgesia) This may be done by: 1- Physiological method (edogenous analgesic system). 2- Pharmacological. 3- Surgical by many methods as cutting of the peripheral nerves. Prefrontal lobectomy may be used in sever cases. It abolishes only the emotional and psychogenic effect of pain but associated with sever personality changes. So, this method is used in terminal stages of severly painful conditions as tumour.

37. THE PAIN CONTROL SYSTEM also called the endogenous analgesic system . consists of special areas in the brain and spinal cord, which when activated can greatly reduce or even completely abolish pain sensation.

38. Location 1-The periaqueductal gray area (PAG area) around the aqueduct of sylvius in the midbrain and pons. 2-The raphe magnus (NRM) nucleus located in the lower region of the pons and upper region of the medulla. 3-The nucleus reticularis paragiganto -cellularis in the medulla. 4- Locus ceruleus (NC) in pons 5- A pain inhibitory complex located in the dorsal horn of the spinal cord (probably in laminae II and III : the substantia gelatinosa of Rolandi).

39. Opioid Peptides Endogenous naturally-occurring physiologic peptides which are similar in structure and function to opium (=morphine). They can bind to the morphine receptors -----> produce long-lasting analgesic effect. The opioid peptides consist of three major groups : The enkephalins , the endorphins , and the dynorphins. Opiate Receptors Three different types of opiate receptors have been characterized : delta ( δ ), kappa (k), and muta ( μ ) Binding of opioid peptides with opiate receptors at specific sites in the nervous system functions to stop synaptic transmission of pain impulses through the central pathways of pain. Can be blocked by naloxone , which is a morphine antagonist

40. Activation of the Pain Control System Clinical (Experimental) Natural (physiological) 1- Electrical stimulation of certain regions of pain control system 2- Local application of opiates (such as morphine) at particular regions in the nervous system. (pharmacological anesthesia) Exposure to severe stress , particularly when associated with strong emotional excitement .

41. PAG Midbrain C.C. Periventricular area of the hypothalamus Limbic system Reticular formation Ascending pain pathway + + + + + Enkephalin --- GABA --- ++ LC NRM GABA --- ++ Enkephalin --- Serotonin +++ Epinephrine +++ Pons Spinal Cord 1 st order neuron in the pain pathway 2nd order neuron in the pain pathway Enkephalin --- How stress activates the pain control system?

43. Enkephalin binds to opiate receptors in: 1- Central terminal of 1st order neuron -----> opening of Cl channel -----> Cl influx -----> hyperpolarization -----> block of Ca influx -----> inhibit release of chemical transmitter from 1st order neuron 2- postsynaptic 2nd order neuron in pain pathway ------> opening of K channels -----> hyperpolarization -----> inhibit their response to the pain chemical transmitter.

44. PAIN GATE CONTROL The sites of synapses along the pain pathway are considered as gates through which pain transmission can be facilitated (if the gate is open) or blocked (if the gate is closed). The main pain gates are: 1- Spinal gate: at the SGR. 2- Brain stem gate : at the nuclei of reticular formation. 3- Thalamic gate: At neurons of PVLNT & intalaminar thalamic nuclei. 3 1 2

45. At the spinal gate: Pain transmission is blocked by: 1- Descending inhibitory impulses through the pain control system activating enkephalin-secreting interneuron (see before) 2- Stimulation of the Large Diameter terminating peripherally in mechanoreceptors, such as tactile receptors or proprioceptors. This may explain why simple maneuvers such as rubbing the skin (thus exciting tactile and pressure receptors), near a painful area is often effective in relieving certain types of pain.

46. Impulses from tactile receptors +

47. 3- Acupuncture Acupuncture has been practiced in China for more than 4000 years as a method for pain relief. Mechanism: 1- needles in appropriate body regions are thought to excite certain sensory neural pathways which feed into the brain stem centers (such as the PAG) involved in the pain control system, with release of endogenous opioid peptides. 2- simultaneous suppression of pain transmission at the spinal pain-gate by acupuncture

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