GM6052 directed studyWelcome To Pain MaterialsPlease wait a moment

ContentInstructionsdefinitions of painTypes of painPain Transmission pathwayAnalgesic drugsExit

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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

Perception of Pain?Perception of pain is dependent upon:Cellular damageReceptor stimulationAscending neural pathwaysSensory cortex arousalConscious awareness of stimulation of pain

Types of painAcute versus chronicNociceptive versus neuropathicSomatic versus visceralReferred versus non referred painSomatogenic versus psychogenicCauses of pain (e.g. cancer, trauma etc)

Acute v chronic

Nociceptive v neuropathicNociceptive pains result from activation of nociceptors (Pain receptors)Neuropathic pains result from direct injury to nerves in the peripheral nervous system

Somatic v VisceralSomatic painSuperficial: stimulation of receptors in skinDeep: stimulation of receptors in muscles, joints and tendons

Visceral painStimulation of receptors in internal organs, abdomen and skeletonOften poorly localised as fewer receptors located in visceraVisceral pain can be referred.

Referred painPain experienced at a point distant to its point of originArea of referred pain is supplied by same spinal segment as actual site of painBrain misinterprets signals as coming from somatic regionsKnowledge 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)

Somatogenic versus psychogenicSomatogenic 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.

Pain pathwayThere are four processes in the pain pathway transductionNoxious stimuli translated into electrical activity at sensory nerve endingsTransmissionPropagation of impulses along spinothalamic pathway. ModulationTransmission is modifiedPerceptionAffective / motivational aspect

Each of these processes present a potential target for analgesic therapy

Transduction - receptorsPain is detected by nociceptors (noci = harmful)Free nerve endings of sensory neuronesFound in all tissues and organs (except brain)Can be classified as either:Unimodal respond to only one type of stimulusPolymodal respond to more than one type of stimuli.

Transduction -Receptor activationWhen cellular damage occurs, tissues release chemicals that stimulate nociceptorsBradykininHistamineSerotonin AcetylcholinePotassium 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

TransductionTRAUMAMechanicalThermalchemical

Overall effect is increased nociceptor activationnociceptorMediatorsBradykininHistamineSerotoninAcetylcholinePotassium ions Prostaglandins (PGE2, PGI2)Substance P

Types of stimuliReceptors respond to injuryThermal excessive heat or coldMechanical tearing, crushing, stretching etcChemicalInflammatory mediatorsLactic acidischemia

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

Transduction - A delta fibres and C fibres

TransmissionA-delta and C ( primary) fibres enter the spinal cord via the dorsal rootThey synapse with secondary neurones in the grey matter of the dorsal horn Marginal zone ( lamina I)Substantia gelatinosa ( lamina II)Lamina VEvidence to suggest that:A-delta fibres synapse in lamina I, II and VC-fibres in lamina I and II

Transmission by primary A-delta and C-fibreslaminaIIIIIIIVVA-Delta or C fibreGrey matter of Dorsal hornSecondary neuron

Pain Transmission PathwayBoth A delta and C nociceptor fibres synapse in the dorsal horn of the spinal cordEvidence 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 neuronesThese tertiary neurones ascend from the thalamus to somatosensory cortex.

Pain Transmission PathwaySome neurones ascend directly to the thalamus allowing rapid analysisThe 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.

Somatosensory cortexSomatosensory 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.htmlhttp://faculty.washington.edu/chudler/flash/hom.html

PerceptionTransduction, transmission, modulation interact to create subjective emotional experience of pain.

Modulation of PainEvidence that pain is inhibited by select neural pathwaysIn dorsal hornInterneurones in the substantia gelatinosa can regulate the conduction of ascending afferent inputSuch interneurons can exert an inhibitory effect on synapses between primary and secondary neuronesThese neurones release opioid peptides (enkephalin, -endorphins and dynorphins) which act on the pre-synaptic terminals of nociceptor fibres to prevent the release of substance P / glutamate

To thalamusInterneuron (releases endogenous opiates e.g.endorphins)interneuronopioidopioid receptorPrimary neuronePrimary neuron (nociceptor)Secondary neuronAfferent pathwayPain transmission blocked by release of opiates

Modulation of PainAction of opioidsPre-synaptic terminals of neurones involved in pain transmission are opioid receptorsWhen 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 () and kappa () receptors)Inhibit Neurotransmitter release by inhibiting voltage dependent calcium channels (delta () receptors)

Modulation of PainInterneurons in the Substantia gelatinosa cells respond to the activity of :Descending pathwaysEndogenous 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

Modulation of Pain descending pathways

The periaqueductal grey matter (PAG) in the midbrain has a role in analgesia and is rich is opioid receptorsPAG 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

Periaqueductal grey matterMedial lemniscusRed nucleusCorticospinal tractNucleus Raphe magnusMedial lemniscus

Corticospinal tract

MIDBRAINMEDULLASPINAL CORDPain modulation descending pathwayTo thalamusnociceptorinterneuronSpinothalamic tract

Gate control theoryStimulation 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 hornThus pain pathway gate is closed by touch.Research into this theory continuesMay be basis of tens and acupuncture along with psychogenic excitation of central analgesia system

Substantia gelatinosa in spinal cordLarge Abeta fibre impulsesSmall Adelta / C fibresPain transmissionCloses pain gateOpens pain gateActions and responsesCentral nervous system pain modulation may increase or decrease painSchematic diagram of gate control theory of pain mechanism

Analgesic drugsAs 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?

Opioid drugsThe term opioid is used to describe a group of drugs that are opium- likeAct on opioid receptors (mainly ) as agonistsOpioids 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 transmissionBind to other receptors affecting chemoreceptor trigger zone, respiratory centre and bowel.

Side effects of OpiatesRespiratory DepressionOpioids bind to receptors which cause reduced sensitivity of central chemoreceptors in medulla to pCO2Bradycardia / HypotensionDepresses cardiovascular centre in medullaPupillary constriction Effect on oculomotor nucleus mediated by parasympathetic nervous systemNauseaActs on chemoreceptor trigger zone in medullaConstipationDecreases motility of gutEuphoriaActs on receptors in reticular formation / limbic system

Opioid agonist and antagonists

NSAIDSAll 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 prostaglandinsThis 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

Action of cyclo-oxygenaseCOX 1 enzymeCOX-2 enzyme

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

Side effects of NSAIDsLinked to inhibition of prostaglandinsGastric 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)

ParacetamolMechanism 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/.

AnaestheticsLocal : block neurotransmission by blocking sodium transport

General: affect ion channels to prevent impulse transmission

Local anaestheticsEpidurals administered to epidural space

Spinal anaethesiaAdministered in intrathecal (subarachnoid) spaceRefer to a text book to see where these spaces are located in the meninges

Local Anaesthetics

Side Effects of Local AnaestheticsEpidurals / spinal anaethesiasSympathetic block - hypotensionUrine retentionMotor block

AmitriptylineActs to Increase levels of norepinephrine and serotoninNorepinephrine and Serotonin act on endogenous descending analgesic pathwayReduces / blocks impulses along pain pathwayUseful in neuropathic pain

Anti-convulsantsMechanism of action unclearDecreases electrical activity along pain pathwayUseful in some types of neuropathic pain

ReferencesGilman S and Newman SW (2002) Manter and Gatzs 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, ElsevierKelly, D.J. (2001) Preemptive analgesia I: physiological pathways and pharmacological modalities. Canadian Journal of Anaesthesia. Vol 48:10, pp1000-1010McCance,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 LivingstoneWeb siteshttp://www.cs.uta.fi/~jh/homunculus.htmlhttp://faculty.washington.edu/chudler/flash/hom.htmlhttp://www.elfstrom.com/arthritis/nsaids/actions.htmlhttp://www.painresearch.utah.edu/crc/CRCpage/definit.html

END OF SESSION

We hope that this has been a useful resource in preparing for the pain seminar

Hyperlink to utah referenceHyperlink reference McCance and Heuther chapter 14 p402.e.g. post therpetic neuralgia after shingles, anaesthesia dolorosa can follow therapeuic transection of sensory nervesThese interneurons exert an inhibitory effect on synapses between first order and second order neurones

Include diagram to demonstrate this actionDraw in diagramPAG small area surrounding central canal1969 reynolds found electrical stimulation of PAG caused analgesia allowing abdominal surgery without anaesthetic.

Include diagram