GM6052 directed study

1. GM6052 – directed study

2. Content Instructions definitions of pain Types of pain Pain Transmission pathway Analgesic drugs Exit

3. Instructions on how to use this resource To proceed through this presentation on pain, advance to the next slide by using the left click on the mouse. The left-click may be used in two ways. Simply left-click on any of the red underlined hyperlinks to jump to information related to the word, phrase or image, alternatively; Left-click anywhere else on the slide to advance to the next slide in the series.

4. Instructions on how to use this resource

5. Instructions on how to use this resource

6. What is pain? Many definitions……….. “ pain is whatever the experiencing person says it is, existing when he says it does” (McCaffery, 1980) “ Pain is an unpleasant sensory or emotional experience associated with actual or potential tissue damage” (International Association for the study of pain 1986) Complex warning sign. Difficult to measure as peoples perception of pain varies Hyperlink to utah referenceHyperlink to utah reference

7. Perception of Pain? Perception of pain is dependent upon: Cellular damage Receptor stimulation Ascending neural pathways Sensory cortex arousal Conscious awareness of stimulation of pain

8. Types of pain Acute versus chronic Nociceptive versus neuropathic Somatic versus visceral Referred versus non referred pain Somatogenic versus psychogenic Causes of pain (e.g. cancer, trauma etc)

9. Acute v chronic Hyperlink – reference McCance and Heuther chapter 14 p402.Hyperlink – reference McCance and Heuther chapter 14 p402.

10. Nociceptive v neuropathic Nociceptive pains result from activation of nociceptors (Pain receptors) Neuropathic pains result from direct injury to nerves in the peripheral nervous system e.g. post therpetic neuralgia – after shingles, anaesthesia dolorosa can follow therapeuic transection of sensory nervese.g. post therpetic neuralgia – after shingles, anaesthesia dolorosa can follow therapeuic transection of sensory nerves

11. Somatic v Visceral Somatic pain Superficial: stimulation of receptors in skin Deep: stimulation of receptors in muscles, joints and tendons Visceral pain Stimulation of receptors in internal organs, abdomen and skeleton Often poorly localised as fewer receptors located in viscera Visceral pain can be referred.

12. Referred pain Pain experienced at a point distant to its point of origin Area of referred pain is supplied by same spinal segment as actual site of pain Brain misinterprets signals as coming from somatic regions Knowledge of different types of referred pain is important in clinical diagnosis because in many visceral ailments the only clinical signs is referred pain. Good section on referred pain can be found in Guyton and Hall (2006)

13. Somatogenic versus psychogenic Somatogenic pain is a pain originating from an actual physical cause e.g. trauma, ischaemia etc Psychogenic pain is pain for which there is no physical cause. It is not however imaginary pain and can be as intense as somatic pain.

14. Pain pathway There are four processes in the pain pathway transduction Noxious stimuli translated into electrical activity at sensory nerve endings Transmission Propagation of impulses along spinothalamic pathway. Modulation Transmission is modified Perception Affective / motivational aspect Each of these processes present a potential target for analgesic therapy

15. Transduction - receptors Pain is detected by nociceptors (noci = harmful) Free nerve endings of sensory neurones Found in all tissues and organs (except brain) Can be classified as either: Unimodal – respond to only one type of stimulus Polymodal – respond to more than one type of stimuli.

16. Transduction -Receptor activation When cellular damage occurs, tissues release chemicals that stimulate nociceptors Bradykinin Histamine Serotonin Acetylcholine Potassium ions Prostaglandins (PGE2, PGI2) Substance P The activity and sensitivity of nociceptors is profoundly altered by such mediators (enhances receptor response to noxious stimuli). See article by Kelly et al ( 2001) for interesting information on this aspect

17. Transduction

18. Types of stimuli Receptors respond to injury Thermal –excessive heat or cold Mechanical –tearing, crushing, stretching etc Chemical Inflammatory mediators Lactic acid ischemia

19. Transduction - A delta fibres and C fibres Nociceptors respond to noxious stimuli and covert energy at the site of the stimulus into neural impulses Nociceptors are terminal endings of primary afferent fibres. These can be classed into two main types myelinated A-delta fibres or non-myelinated C fibres When the threshold level of the stimulus is reached, then depolarisation occurs along these fibres in the form of action potentials

20. Transduction - A delta fibres and C fibres

21. Transmission A-delta and C ( primary) fibres enter the spinal cord via the dorsal root They synapse with secondary neurones in the grey matter of the dorsal horn Marginal zone ( lamina I) Substantia gelatinosa ( lamina II) Lamina V Evidence to suggest that: A-delta fibres synapse in lamina I, II and V C-fibres in lamina I and II

22. Transmission by primary A-delta and C-fibres

23. Pain Transmission Pathway Both A delta and C nociceptor fibres synapse in the dorsal horn of the spinal cord Evidence suggests that neurotransmitters released at this point include substance P, glutamate, calcitonin gene-related peptide (CGRP). Secondary neurones cross the cord and ascend through the antero-lateral spinothalamic tract to the thalamus where they synapse with tertiary neurones These tertiary neurones ascend from the thalamus to somatosensory cortex.

25. Pain Transmission Pathway Some neurones ascend directly to the thalamus allowing rapid analysis The spinothalamic tract also sends collaterals to reticular formation, hypothalamus and other limbic structures (associated more with C-fibres and slow pain) This more indirect pathway mediates arousal and emotional reactions to pain. It is also responsible for somatic and autonomic motor reflexes.

26. Somatosensory cortex Somatosensory cortex is involved in the localisation and identification of pain. Check out these web sites which demonstrate the homunculus and sensory perception. http://www.cs.uta.fi/~jh/homunculus.html http://faculty.washington.edu/chudler/flash/hom.html

27. Perception Transduction, transmission, modulation interact to create subjective emotional experience of pain.

28. Modulation of Pain Evidence that pain is inhibited by select neural pathways In dorsal horn Interneurones in the substantia gelatinosa can regulate the conduction of ascending afferent input Such interneurons can exert an inhibitory effect on synapses between primary and secondary neurones These neurones release opioid peptides (enkephalin, ß-endorphins and dynorphins) which act on the pre-synaptic terminals of nociceptor fibres to prevent the release of substance P / glutamate These interneurons exert an inhibitory effect on synapses between first order and second order neurones Include diagram to demonstrate this actionThese interneurons exert an inhibitory effect on synapses between first order and second order neurones Include diagram to demonstrate this action

30. Modulation of Pain Action of opioids Pre-synaptic terminals of neurones involved in pain transmission are opioid receptors When these receptors are activated by opioid peptides or other agonists the release of Neurotransmitters (Sub P, glutamate etc) is decreased. Achieved in two ways: Inhibit Neurotransmitter release by activation of potassium channels on pre-synaptic terminal (mu (µ) and kappa (?) receptors) Inhibit Neurotransmitter release by inhibiting voltage dependent calcium channels (delta (d) receptors)

31. Modulation of Pain Interneurons in the Substantia gelatinosa cells respond to the activity of : Descending pathways Endogenous analgesic pathway. Norepinephrine, serotonin and opioids are involved in brainstem inhibitory pathways that modulate pain in the spinal cord. Afferent fibres entering the cord (gate control theory) Touch receptors v pain receptors Draw in diagramDraw in diagram

32. Modulation of Pain – descending pathways The periaqueductal grey matter (PAG) in the midbrain has a role in analgesia and is rich is opioid receptors PAG receives impulses from many brain regions inc. hypothalamus, cortex and thalamus. Stimuli include stress, exercise, acupuncture. Main neuronal pathway activated by PAG stimulation extends first to nucleus raphe magnus (NRM) in the medulla and then to dorsal horn interneurones. Enkephalins are released at these synapses and inhibit nociceptor NT release PAG small area surrounding central canal 1969 reynolds found electrical stimulation of PAG caused analgesia allowing abdominal surgery without anaesthetic. Include diagramPAG small area surrounding central canal 1969 reynolds found electrical stimulation of PAG caused analgesia allowing abdominal surgery without anaesthetic. Include diagram

34. Gate control theory Stimulation of large touch sensory fibres ( type A beta fibres) can depress transmission of pain signals from the same body area. Thought that A beta fibres stimulate endorphin releasing inteneurons in dorsal horn Thus pain pathway ‘gate’ is closed by touch. Research into this theory continues May be basis of tens and acupuncture along with psychogenic excitation of central analgesia system

36. Analgesic drugs As mentioned previously the aim of analgesic drugs is to inhibit the processes of pain transmission. Drug types considered in this presentation include opioids, NSAIDS, paracetamol, local anaesthetics, amitriptyline and anticonvulsants. Can you identify where each group act on the pain pathway?

37. Opioid drugs The term ‘opioid’ is used to describe a group of drugs that are opium- like Act on opioid receptors (mainly µ) as agonists Opioids excite neurones in periacqueductal grey matter and thus activate the descending analgesia pathway. Also act directly on pre-synaptic terminal of nociceptor neurons in dorsal horn and inhibit pain impulse transmission Bind to other receptors affecting chemoreceptor trigger zone, respiratory centre and bowel.

38. Side effects of Opiates Respiratory Depression Opioids bind to receptors which cause reduced sensitivity of central chemoreceptors in medulla to pCO2 Bradycardia / Hypotension Depresses cardiovascular centre in medulla Pupillary constriction Effect on oculomotor nucleus mediated by parasympathetic nervous system Nausea Acts on chemoreceptor trigger zone in medulla Constipation Decreases motility of gut Euphoria Acts on receptors in reticular formation / limbic system

40. NSAIDS All nociceptors can be sensitised by prostaglandins. i.e. prostaglandins greatly enhance the receptor response to noxious stimuli NSAIDs act by suppressing cyclo-oxygenase, an enzyme involved in synthesis of prostaglandins This blocks inflammatory process (anti- inflammatory) and reduces sensitivity of nociceptors (analgesic) A good website giving more detail on this is as follows: http://www.elfstrom.com/arthritis/nsaids/actions.html

41. Action of cyclo-oxygenase

42. NSAIDS: mode of action NSAIDS block both COX-1 and COX-2 This accounts for most of the side effects of NSAIDS Different types of NSAIDS have different specificities for COX-1 and COX-2 This contributes to differences in side effects between the NSAIDS.

43. Side effects of NSAIDs Linked to inhibition of prostaglandins Gastric problems – prostaglandins have a role in protecting gastric mucosa and also regulate blood flow to gastric mucosa ( inhibition of COX-1) Renal failure – prostaglandins influence renal blood flow (inhibition of prostaglandin reduces glomerular filtration as well as causing sodium retention) Aspirin – anti-coagulant as inhibits platelet aggregation (inhibition of COX-1)

44. Paracetamol Mechanism not certain – may be weak inhibitor of the synthesis of prostaglandins or act on descending analgesic pathway. Read this article to find out more – you can access it online!!! Graham,GG and Scott, KF (2005). Mechanism of action of paracetamol American Journal of Therapeutics Jan-Feb;12(1):46-55/.

45. Anaesthetics Local : block neurotransmission by blocking sodium transport General: affect ion channels to prevent impulse transmission

46. Local anaesthetics Epidurals – administered to epidural space Spinal anaethesia Administered in intrathecal (subarachnoid) space Refer to a text book to see where these spaces are located in the meninges

47. Local Anaesthetics

48. Side Effects of Local Anaesthetics Epidurals / spinal anaethesias Sympathetic block - hypotension Urine retention Motor block

49. Amitriptyline Acts to Increase levels of norepinephrine and serotonin Norepinephrine and Serotonin act on endogenous descending analgesic pathway Reduces / blocks impulses along pain pathway Useful in neuropathic pain

50. Anti-convulsants Mechanism of action unclear Decreases electrical activity along pain pathway Useful in some types of neuropathic pain

51. References Gilman S and Newman SW (2002) Manter and Gatz’s Essentials of clinical neuroanatomy and neurophysiology (10th Ed). FA Davis. Graham,GG and Scott, KF (2005). Mechanism of action of paracetamol American Journal of Therapeutics Jan-Feb;12(1):pp46-55. Guyton,A.C. and Hall,J.E. (2006) Textbook of Medical Physiology. Philadelphia, Elsevier Kelly, D.J. (2001) Preemptive analgesia I: physiological pathways and pharmacological modalities. Canadian Journal of Anaesthesia. Vol 48:10, pp1000-1010 McCance,K.L. and Heuther,S.E. (2002). Pathophysiology: The Biological basis for Disease in Adult and Children. St.Louis, Mosby. Rang et al (2003) Pharmacology. Edinburgh. Churchill Livingstone Web sites http://www.cs.uta.fi/~jh/homunculus.html http://faculty.washington.edu/chudler/flash/hom.html http://www.elfstrom.com/arthritis/nsaids/actions.html http://www.painresearch.utah.edu/crc/CRCpage/definit.html

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