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Pain (PAIN AND PLEASURE (Opioids (Endogenous (The reason these synthetic…

- - - - Morphine analgesia (clinical analgesia) requires the MOP opioid receptor. This receptor also causes the pleasure, withdrawal and side effects
      - Mu (MOP), KOP, DOP, NOP; 7TM GPCR
    - - The reason these synthetic opioids work is bc we have endogenous ones like endorphin which are neuropeptides.
      - Endorphin is quite localised to the midbrain
      - MOP, DOP, KOP and enkephalin and dynorphin are found in the entire pain network
    - - The Opioid analgesics differ in their structure, selectivity, efficacy, side effects
      - Morphine and heron are strong opium associates and codeine is a weak one
      - Injecting an opioid into the PAG activates a descending relay and prevents pain information from entering the spinal cord and moving to the brain
  - - - Signal directly to spinal cord > reflex withdrawal
      - Nociceptors (ion channels) respond to noxious stimuli: mechanical, thermal, chemical (polymodal ones detect a combination of stimuli types)
      - Visceral pain is referred due to somatic crossover due to similar embryological origins e.g. appendix referred to abdomen
      - Spatial arrangement of dermatomes > nociceptive afferent fibres > cell body in DRG > synapse to dorsal horn of spinal cord
      - Microneurography shows that the size of receptive field causes changes in freq of AP given the same stimulus intensity
      - Different to mechanosensation bc this has transmission from the receptor cell to the sensory neuron allowing complex firing whereas c fibres have their own receptors
      - Factors like heat, cold, prosta, brady, cytokines can drive AP or change transduction e.g. more sensitive
      - The larger the electrical stimulation of a nerve, the more nerve fibre types it recruits and the more pain (A-alpha,-beta,-delta, C). First pain is is from A fibres and is faster due to myelin, slow and sustained second pain is from unmyelinated C fibres
      - Somatosensory system
        
        From skin, touch goes up spinal cord to brain stem and then to thalamus and then somatosensory cortex via dorsal column nuclei
        
        Pain from skin on c fibres, first synapses at the (outer laminae of the) dorsal horn and then thalamus and then somatosensory cortex
        
        ^ This is the spinothalamic tract and allows us to know where and how much pain is being perceived after cortical processing (can be separated from the reflex, without pain)
        
        50% of the c fibres are peptidergic (P, CGRP) and bind NK1-R
    - - Persists over time due to complex activation of spinal cord
    - - Chronic pain
        
        Predisposition to chronic neuropathic pain: potsherdetic neuralgia, cancer, surgery/amputation, burns
        
        Neuromas can form when nerves are injured and there can be spontaneous firing and cross fire between neurons MESSED UP
        
        Persists for more than 3 months following surgery or injury, due to changes in the nervous system
      - Embedded pain from NS overstimulation after sensitisation
      - GO TO BLUE
  - - - Emotional areas of the brain are the thalamus and hypothalamus. Hippocampus regarded as an anterior part of the thalamus. A feeling is felt after sensory perception via the cingulate cortex and the hypothalamus can cause a bodily response
      - Limbic system
        
        Loop of interconnected brain regions from the primitive cortex: hippo, cingulate, amygdala (fear) and the deep brain
        
        The hypothalamus initiates physical response to emotion: musculoskeletal, autonomic activity e.g. heart, hormone release e.g. stress
      - Emotion constitutes an internal CNS state triggered by internal or external stimuli; scale of pleasant and aroused
      - Facial expression is used as a surrogate measure of pain in those who cannot speak. Activations of the facial muscle in different ways represents emotional states; cingulate cortex
      - Pain pathways project to somatosensory and limbic regions of the brain
      - Fear
        
        Conditioning can occur where the perception of a sound can be synced up to the perception of pain, until the sound alone can elicit the somatosensory response of shock
        
        Fear causes endogenous analgesia to make us less responsive to the following noxious stimuli; 30% analgesic effect on placebo
        
        Fear is developed in the amygdala
        
        Endogenous opioids bind receptors and act along the descending pathway to limit pain sensation
    - - Closely related to the dopaminergic system in the brain
      - Reinforcers
        
        Positive reinforces: (rewards, S+) increase frequency of behaviour which leads to acquisition
        
        Negative reinforces: (punishers, S-) decrease freq of behaviour which leads to encounter and increase behaviour leading to avoid
        
        Goal directed behaviour: behaviours controlled by the representation of a goal or an understanding of how a behaviour may work toward goal attainment
      - We can make predictions and cause increase in pleasure through expectation. Evaluation of an experience while it happens causes peaks in pleasure and a fall in pleasure could result from an incorrect prediction
      - Pain in the presence of pleasure can reduce the perception of pain, unless in the presence of opioid antagonists
      - EMOTION, COGNITION AND PAIN ARE INTERRELATED AND INFLUENCE EACH OTHER
- - - - Peripheral sensitisation is a very excited state of hyperalgesia (left shift), protection since it reduces pain threshold (allodynia) until healed. Occurs by up regulating ion channel nociceptors.
      - Sensitisation occurs
      - Requires activation and has plasticity since it can be re-shaped and is different in individuals due to polymorphisms
    - - Inflammation from injury > receptor activation (transduction) > neural conduction > spinal cord/brain modulation > pain
      - Adelta fibres are for fast acute localised sharp pain (myelin,faster)
      - C fibres are for slow aching burning throbbing pain. this+^ NOCI
      - Modulation required to not overload the brain so signals are attenuated by endogenous opioid endorphins. Opioid receptors found in spinal cord and decrease NT release pre-synaptically and hyper polarise DRN post e.g. morphine. Can bind PAG to cause analgesia
      - Excitation: sustained and severe pain removes Mg plug from NMDA causing opioid resistance and sensitisation (also helped by astrocytes and microglia)
      - Modulation II: rapid conducting feedback loop between ascending and descending pathways where inhibition of spinal dorsal horn dampens incoming pain signals, done by acting on noradrenergic and 5HT3 fibres e.g. amitryptilline
  - - - Paracetamol/aspirin (anti platelet)
      - NSAIDs e.g. ibuprofen
      - Opioids
        
        Morphine is the main one. Can use a patient controlled analgesia machine so they can give themselves 1mg of morphine when they feel pain. Morphine is soluble so can dissolve in CSF and cause problems in the brainstem
      - Adjuvants like antidepressants and gabapentanoids (first line for neuropathic pain unresponsive to normal analgesia)
      - Limitations: individual, tolerance, addiction, side effects
    - - Drug metabolism could be different
      - Absence of Na channels 1.7 means no pain
      - Stargazer gene causes susceptibility to neuropathic pain
    - - General anaesthesia: remove CNS pain perception
- - - - Fatigue, diarrhoea, vomiting, somnolence, abnormal liver (metabolised here)
- - - - Pharmacotherapy
        
        Suboxone is buprenorphine (partial agonist of opioid receptors) and naloxone (blocks opioids)
        
        Opioid replacement therapy: methadone, suboxone. Reduces mortality, morbidity, hospitalisation, criminality
      - Rehabilitation
    - - Abuse deterrent formulations means changing the administration of drug makes it useless, e.g. cannot inject or snort
      - Biggest source of black market opioids is from legitimate medicinal supply
    - - Necrosis, infarction from chronic injection of heroin and impurities
      - Treating heroin addiction sometimes involves other opioids to give similar effect to help them get off it
      - Highest disease burden attributable to any illicit drug
      - Hospitalisation from heroin has dropped but other opioids risen
      - Increasing codeine use for analgesic increases paracetamol and ibuprofen use since in combo usually and these are toxic
- - - - This inhibits pain TRANSMiSSION in the spinal cord
      - Approved when severe pain and tolerant of other treatments.
      - Ziconotide (omega-conotoxin). Highly selective blocker of N-type calcium channels of the Adelta/ C fibres before they synapse to dorsal horn neurons. Found in Conus Magnus snail
      - Infusion pump into thecal space (CV side effects if intravenous; bradycardia, decrease MAP; effects baroreflex, dizziness if hits supraspinal area) with no addiction
    - - Savitex
        
        Spray under tongue, lipid soluble, into buccal circulation. Well tolerated, little side effects
        
        In neuropathic pain, 41% over baseline, 20% over placebo. Maintained decreased pain for 6 months and increase sleep quality and quantity
        
        THC (analgesic, apetite, anitmimetic, psychoactive) + CBD (analgesic, relaxant, anitoxidant, antipsychotic)
      - CB1R
        
        CNS: hypo, hippo, cortex, cere; low in brainstem (no cardiotoxicity effects unlike opioids)
        
        Periphery: sensory neurons, vasculature, gut, urogenital
        
        Stimulation causes: analgesia, anti-emesis, apetite stimulation
        
        Inhibits peripheral nerves transmission via afferents (like MOP). 2. In the dorsal horn, inhibit relay neurons (pre-synaptically inhibit N-type Ca on afferents to block NT release, and post- hyperpolerise by activating K channels. 3. Enhance descending modulatory pathway via alpha2 adrenoceptor pathway DECREASE EXCITABILITY
        
        CB2R DECREASE INFLAMMATION
      - THC and CBD the only clinically well characterised phytocannabinoids
      - THC active principle of cannabis. CB1R in brain and peripheral nerves. CB2R in immune cells (microglia). Anandamide is endogenous mediator and also endocannabinoids (all fat soluble, BBB)
      - Medical marijuana for children with epilepsy, cannabadiol.
      - CBD
        
        Has little affinity for CB1/2R. Instead, inhibits FAAD which breaks down anandamide (endogenous cannabinoid acting on CB1R) => antiinflamm via adenosine A2aR
        
        Opposes THC bind to CB1R, no psychoactive effects
        
        CBD-enriched cannabis for intractable epilepsy decreased seizures; better alertness, mood, sleep. Caused some drowsiness, fatigue
      - Nabilone
    - - Pregabalin
        
        More potent, faster, more predictable (90% bioavailability) aa "modulator" of the Ca channel. Cross BBB
        
        Binding decreases calcium influx at pre-synaptic terminals (the Adult or C fibre) in hyper excited neurons
        
        Also decreases release of excretory neurotransmitters (glutamate, substance P, noradrenaline) decreasing post-synaptic (dorsal horn neuron) stimulation in dorsal horn
      - Gabapentin (old) and pregabalin (new); originally anti-epilepsy by mimicking GABA neurotransmitter
      - First line, high efficacy and low drug-drug interactions. Combination of different mechanism drugs is better than either at low dose (gabapentin, morphine) and reduces side effects, tolerance
  - - - Dorsal horn
        
        When trophic support is withdrawn, C fibres lost and Abeta fibres replace. High excitability also causes loss of inhibitory neurons
        
        Peripheral damage ^ causes reorganisation in dorsal horn
      - Periphery
        
        Cytokines from macro and schwann, and neurotrophic try to fix injured nerve tissue
        
        ^ causes upregulation of Nav1.3 channels (genetic expression) => fast recovery > enhanced cellular excitability > ectopic AP activity
        
        Functional and structural changes of afferents and CNS
      - Begins with trivial injury to nervous system but is not healed properly and lasts indefinitely and can worsen. Not helped by many analgesics like strong opioids
      - Voltage gated calcium channels
        
        Alpha2delta increases the time until inactivation, increasing Ca current. Upregulated in DRG in neuropathic pain (>hyper excitability)
        
        4 subunits; alpha1 makes the pore. Alpha2delta is extracellular and ancillary (only CNS) to which gabapentin and pregabalin bind
    - - Nociceptive basis (chronic arthritis), neuropathological basis (phantom limb pain), idiopathic (not well defined: abdominal, headache)
      - Neuropathic (pins and needles, shooting, burning) is damage to nociceptive pathways. Hypersenstitivty, hyperalgesia, allodynia
      - Nociceptive can be superficial (burning, stinging) or deep (dull aching) somatic, or visceral (deep dull)