5Nociception Nociception –the perception of a noxious stimulus Pain – the subjective ‘feeling’ due to a noxious stimulusAnalgesia – the modulation of nociception or painTransduction of a noxious stimulus into electrical activity in appropriate nerve endingsTransmission of the electrical signal through nerves, to the spinal cord and the brainPerception of the noxious stimulus in brain areas, and the conscious ‘feeling’ of painModulation of signal at various levels (analgesia)
6Levels of nociception Transduction Noxious stimuli activate peripheral nociceptorsMostly polymodal, responding to mechanical, thermal and chemical stimuliSome unimodalResponses mediated through histamine, prostoglandins, bradykinin etc.Peripheral transmissionPeripheral nociceptive fibres enter spinal cord through the dorsal root and terminate in the dorsal hornSynapse in the dorsal horn with both ascending axons and spinal interneuronesNeurotransmitters at the spinal cord: glutamate and substance P
7Central transmissionAscending axons cross midline and ascend through anteroelateral column of the spinal cordTerminate in the ventral posterior nucleus of the thalamusCollateral terminations in the brain stemProjections from brainstem to thalamusThalamus projects to somatosensory cortexAlso to cingulate cortexReciprocal connections between somatosensory and cingulate cortices.Figures from :Carlson: Physiology of Behaviour
9‘Pain’ perceptionPerception of pain is probably in the cingulate cortexCingulate cortex is activated in people during illusory painPain is a subjective experience based on the information received from nociceptive fibresThe brain can be fooled into thinking something is painful, even though no tissue damage has occurredMechanism of pain perception is very poorly understood
10Opium and opioid drugsOpium is one of the earliest known drugs used by manComprises the dried sap of the opium poppySedative and analgesicWell known to ancient GreeksTwo main active components of opiumMorphine (~10%)Codeine (~0.5%)Morphine is poorly absorbed orally.Hence, to produce central effects, it is injected.Other opioid drugs.Heroin, methadone.
11MorphineMorphine acts through binding sites in the brain and spinal cordWhat are the endogenous receptors which morphine acts on?At first believed to act as an antagonist at one or more stages of the pain pathwayBut effects of morphine are blocked by naloxoneSuggests that morphine is an agonist not an antagonistMorphine is not endogenousEndogenous opioids were isolated in 1970sEnkephalins, endorphins, dynorphins
12Opioid AnalgesiaMorphine injected into lateral ventricles relieves severe paineffective at doses 10-fold lower that for systemic injectiontherefore acting in the brainIntracerebral injection of morphine induces analgesiaperiaqueductal grey matter (PAG)periventricular grey matter (PVG)rostroventral medulla (RVM)These effects are blocked by naloxoneNaloxone injected into PAG, PVG or RVM partially reverses analgesic action of systemically administered morphine
13Stimulation Produced Analgesia Electrical stimulation of localised brain areas suppress pain perceptionperiaqueductal grey matter (PAG)periventricular grey matter (PVG)rostroventral medulla (RVM)Analgesia is an active processHow does stimulation produced analgesia relate to opioid analgesia?
14Similarities between opiate analgesia and stimulation produced analgesia Effective loci are the same in each case (i.e. PAG, PVG, RVM)Both are blocked by naloxoneCombining sub-analgesic levels of both produces analgesiaCross-tolerance develops between the two.Both effects cause blockade of spinal reflexestherefore mediated at the level of the spinal cordBoth effects activate the same descending spinal pathwaydorsolateral funiculusTherefore stimulus produced analgesia is mediated through opioid mechanisms
15Levels of opiate analgesia Supraspinalopioid receptor activation in brain stemmediated via spinal cord mechanismsmu-receptor mediated (i.e. enkephalins)Spinalopoid receptors activation in spinal corddelta- & kappa- receptor mediated (enkephalins & dynorphins)Hormonalstress-induced analgesia is reversed by naloxonealso reversed by removal of adrenal glandsmechanism is unclear
16Non-opiate analgesia Brain stem Noradrenaline and 5HT modulate analgesiaEspecially in PAG and PVGMechanism not clearly understoodSpinal cordNoradrenaline injected into spinal cord blocks responses to noxious stimuli5HT injected into spinal cord is analgesicblocks spinal cord nociceptive neuronesblocks spino-thalamic neurones
17Ascending nociceptive pathway Control of analgesia(+)(+)(+)Morphine/SPACentral grey matter(+)(+)RaphenucleiRostroventralmedullaAscending nociceptive pathway(+)Na5HT(-)(-)Nociceptive neuroneEnk(-)(+)
18Alternative methods of analgesia Transcutaneous electrical nerve stimulation (TENS):Alters nociceptive signal to brain, or brain’s perception of painMechanism unclear but may activate endogenous opiate systemsAcupunctureGreater than 80% increase in pain thresholdIncreased enkephalin levels in the brainIncreased biosynthesis of enkephalinsEffects were enhanced by enkephalinase inhibitorsMay be mediated via enkephalin release in PAG and PVGPlacebo : may activate endogenous pain-control systemsHypnosis : alters brains perception of painStress : both opiate and non-opiate mechanismsCognitive : may activate endogenous pain-control systems
19SummarySensory perception occurs at peripheral modality-specific receptorsInformation transmitted to the brain through cranial or spinal nervesMakes connections in brainstem and thalamusInformation enters cortex at unimodal primary sensory corticesHierarchical processing occurs in unimodal association corticesHighly processed unimodal signals enter multimodal association cortex, where sensory integration occurs