PAIN

Question 1

What is pain?

Answer 1

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” -> Why is pain important: it promotes of avoidance of situations which may decrease biological fitness, it promotes resting behaviour that either enhances recovery following injury or modifies behaviour so that further injury or death become less likely.

Question 2

What are nociceptors?

Answer 2

Specialized neurons, sensory neurons (specific to pain), free nerve endings, synapse in spinal cord to ascending, neurons to brain.
Reflex action -> Lift your foot off it -> spinal reflex, withdrawing from painful stimuli.

Question 3

Different receptors

Answer 3

Free nerve endings contain receptors sensitive to noxious stimuli: intense pressure stretching, striking, pinching. -> high threshold mechanoreceptors (heat, acids (damage) and capsaicin (chilli pepper)), -> vanilloid receptor, TRP channels (temperature-gated channels) damage (ATP release)) -> purinergic receptors -> Channels open, neuron depolarizes, fires action potentials

Question 4

Stepping on lego scenario

Answer 4

What is your response? Lift your foot off it, Feel sharp pain, you recognise as being in your foot, Feel a slower throbbing pain, Hop up and down
Response -> detect pain, activate sensory receptors and nociceptors -> pain detectors -> specialized neurons -> nociceptors. While stepping on lego -> Lift your foot off it -> Plus signals to the brain that make you conscious of it -> Feel sharp pain, you recognise as being in your foot -> Feel a slower throbbing pain (different neurons – different speeds of message), paths to different brain areas – different roles -> Hop up and down a bit.

Question 5

How do nociceptors conduct electrical signal?

Answer 5

Nociceptors conduct electrical signal to spinal cord (primary afferent – two types)
A fibres-> lightly myelinated, medium diameter, first pain -> fast localization of painful stimuli. C fibres -> unmyelinated, small diameter -> second pain -> provide the continuing dull ache, poorly localized.
Compared with Aa and Ab fibres (normal proprioceptors) myelinated, large diameter.

Question 6

Two paths into brain (for pain)

Answer 6

to somatosensory cortex via the thalamus -> encode the sensory components -> sensory discrimination -> tell you “Where” it hurts. to ‘emotional’ cortex (insula and cingulate) via the thalamus -> encode the emotional components -> unpleasantness -> negative affect

Question 7

What happens if you have caused a real damage?

Answer 7

Pain can be protective to allow you to heal -> Pain sensitization processes -> Hyperalgesia - noxious stimuli produce exaggerated pain sensation -> Allodynia- non-noxious (no nociceptors) stimuli produce pain sensation (e.g. touching sun-burnt skin) -> Peripheral sensitization: inflammatory response in and around injured tissue -> Central sensitization: neuroplastic changes at synapses in spinal cord.

Question 8

Peripheral sensitization?

Answer 8

Chemicals released -> as a result of tissue damage (e.g., releasing neuropeptides, ATP, H+) -> from the nociceptors -> as part of the inflammatory response -> directly activate and/or modulate ion channels in nociceptor terminals -> neuropeptides - substance P and CGRP (calcitonin gene related peptide), released from nociceptor neurons which trigger: vasodilation, plasma extravasation (leakage of proteins and fluid from capillaries) -> activation of Mast cells and neutrophils.

Question 9

What is in the inflammatory soup?

Answer 9

The inflammatory soup -> Histamine (mast cells), Nerve Growth Factor (mast cells), Serotonin (platelets), Proteases (cleave extracellular, peptide to bradykinin, COX enzymes (cyclo-oxygenase), convert arachidonic acid, (lipid) to prostaglandin.

Question 10

Modulation of the nociceptor activation

Answer 10

Components of the inflammatory soup, Bradykinin, NGF and Prostaglandin feedback back to their own metabotropic receptors on the nociceptor neurons. VR1 receptor is phosphorylated, and threshold changes so opens at lower temperatures -> A sensory nerve specific (SNS) Na+ channel is phosphorylated so threshold voltage for firing is decreased, making the nociceptor more excitable-> Nociceptors become hypersensitive to stimulation -> peripheral sensitization.

Question 11

Why increase pain sensitivity?

Answer 11

‘Good pain’ -> Reminds you that you have hurt yourself, Protecting injured area for recovery without further damage. Congenital disorders where people have no pain perception -> no signals to indicate to avoid painful stimulus, low life expectancy. -> An SCN9A channelopathy causes congenital inability to experience pain.

Question 12

What are Gate control theory?

Answer 12

Hopping up and down, rubbing, blowing! -> stimulation of Aa or Ab fibres in vicinity of injury activates interneuron in dorsal horn which inhibits spinothalamic neuron from firing. competition between excitation (from nociceptor) and inhibition (from proprioceptors) Prevents pain signals getting to brain. Competition.

Question 13

Treatment of burn patients

Answer 13

Changing dresses, physiotherapy etc. very painful -> Opioid treatments but issues with dosing/tolerance etc.-> Virtual reality environment (snow world) -> patient’s pain ratings reduced by 30-50% -> reduction in time spent thinking about pain, pain intensity and in how unpleasant they found pain. Central processes -> reduced activity in pain processing areas of brain when treatment in presence of virtual reality (VR) -> somatosensory cortex -> anterior cingulate and insula + thalamus. Sensory process and emotional process. Reduction in the activity of pain stimulation.

Question 14

Stress-induced analgesia

Answer 14

Adaptive induced analgesia -> adaptive response to down-regulate pain -> central mechanism triggers descending regulation of pain circuitry to inhibit pain signals arriving in the brain ->One mechanism involves the release of endogenous opioids -> naloxone challenge (opioid antagonist) blocks the analgesic effect. (Example –soldiers escaping from danger with bd wounds – don’t feel pain till in safety. Same pathway with opioid drugs.

Question 15

Descending modulation of spinal neurotransmission

Answer 15

Showing how you can have activity from the brain to spinal cord, ascending and descending pathways. outputs from somatosensory cortex via thalamus to midbrain -> hypothalamus to midbrain -> midbrain to medulla -> medulla into spinal cord -> variety of onward projections (opioid peptide, serotonin, noradrenaline) -> to dorsal horn of spinal cord modulation (“gating”) of transmission by dorsal horn nociceptive neurons.

Question 16

What is the descending inhibitory control?

Answer 16

The endogenous opiate system, Brain overrides pain signals, switches them off in spinal cord, Opioids acting at inhibitory metabotropic receptors. Multiple sites of action: 1) opioids can inhibit inhibitory neuron in the PAG (e.g. allow excitation) -> PAG neurons disinhibited (fire) and activate serotonergic neuron from raphe which act to excite enkephalinergic neurons in spinal cord -> release of enkephalin acts at opioid receptors on the nociceptor terminal in dorsal horn inhibits firing of spinothalamic neuron (pre and postsynaptic effect).

Question 17

Active descending modulatory pain pathway

Answer 17

Active -> glutamatergic projection from cortex to PAG (firing), opiodiegic interneurons in PAG (excited), GABAergic projection from PAG to Raphe (inhibited), disinhibited serotonergic projection from Raphe to dorsal horn (excited). Opiodergic interneurons dorsal horn (excited), pre and postsynaptic inhibition of spinothalamic ascending projection.

Question 18

Inactive descending modulatory pain pathway

Answer 18

Inactive -> Glutamatergic projection from cortex to PAG (not firing) -> When no pain modulation required the GABAergic projection from PAG to Raphe fires tonically - keeping system switched off -> Opiodiergic interneurons in PAG (not firing), GABAergic projection from PAG to Raphe (firing), Serotonergic projection from Raphe to dorsal horn (inhibited), Opioidergic interneurons in Dorsal horn (not firing), Pre and postsynaptic inhibition of spinothalamic ascending projection.

Question 19

Reducing pain part 1

Answer 19

Drugs and techniques producing analgesia -> Chronic pain (neurogenic - nocigenic) -> Chronic pain treatments and underlying mechanisms. Acute pain – we know biology so can target directly. Potential sites of action for local anesthetics, NSAIDS, opiates, and cannabinoids to mediate analgesia. Sodium channel blocker stops generation of action potentials, Opiate and/or cannabinoid receptors (Gi coupled) activated leading to inhibition of adenylyl cyclase, NSAID blocks synthesis of prostaglandin.

Question 20

Reducing pain part 2

Answer 20

Capsaicin -> active ingredient in chili, agonist of TRP channels, Possible mechanism of actions desensitizes receptors (stop fluxing ions), massive release of Substance P in Spinal cord, depletion of substance P blocks central sensitization. Opiates e.g. morphine, codeine, fentanyl -> Mechanism of action -> agonists of the endogenous opioid system, tap into bodies own system of pain regulation -> multiple sites of action -> peripherally, spinal cord, centrally.

Question 21

What are endogenous opioid system?

Answer 21

Other methods of tapping into the endogenous opioid system, Electrical stimulation of PAG - clinically significant pain relief (stimulates release of opioids?), Acupuncture - (a bit like gate control theory), some evidence can be blocked by naloxone, implicating opioid system, Placebo - effects can be blocked with naloxone(the power of suggestion) Non - opioid mechanisms multiple ways the brain can modulate pain signals and information e.g. some stress induced analgesia is not blocked by naloxone endocannabinoids?

Question 22

Cannaboid system and stress-induced analgesia

Answer 22

Endocannabinoids, 2 arachidonoyl glycerol (2-AG) and anandamide, act at CB1 receptor -> Levels of 2-AG and anandamide in PAG increase with stress -> Injection of CB1 agonist into PAG is analgesic -> Injection of CB1 antagonist into PAG blocks stress induced analgesia. Multiple target mechanisms for treating pain. More research - individual treatments etc.

Question 23

Possible mechanisms leading to chronic pain

Answer 23

Peripherally -> sensitization of peripheral neurons -> increased activity of damaged axons and sprouting. Centrally -> hyperexcitability of central neurons -> reorganization of synaptic connectivity in spinal cord -> disinhibition - removal of tonic descending inhibitory control.

Question 24

What is chronic pain?

Answer 24

Chronic pain -> Nerve damage causes resprouting and new synapse formation in dorsal horn, Ab fibres synapse onto nociceptive neurons. Excess glutamate release during painful stimulus results in excitotoxicity, loss of inhibitory interneurons, no brake on excitation.

Question 25

Management of chronic pain

Answer 25

Complicated as many other associated problems that need to be treated in conjunction e.g., primary disease, depression, sleep disturbance, fatigue. 80% of depressed people are present at clinic with physical symptoms. Drugs for chronic pain include, tricyclic antidepressants, anticonvulsants, NMDA antagonists, cannabinoids etc.

Question 26

Psychology of pain

Answer 26

Pain perception is very individual, Identical injury - chronic pain does not manifest in every patient, what kind of factors may influence this how brain processes may affect pain perception etc. Biological factors, Gender, Psychopathology, Social factors, Personality, Cultural factors, Situation and circumstance, Beliefs about pain Genetics -> Disorders with genetic component e.g. congenital pain disorders, migraine, temporomandibular joint disorder. Genetic variability in components of system e.g., failure to increase levels of analgesic peptides (NPY), marked decline in GABAergic function, accentuated sympathetic responses.

Question 27

Pain interactions with other systems

Answer 27

Interactions with other systems -> e.g., irritable bowel syndrome, brain-gut dysfunction, Sex differences in pain perception: Some disorders associated with a particular sex, e.g., cluster headaches – male. migraine, TMJ, Rheumatoid Arthritis, Fibromyalgia – female

Question 28

Pain perception in females

Answer 28

Pain perception (thresholds) differ with sex Females report: -> more intensive acute pain -> more chronic pain -> greater intensity -> pain in more bodily areas -> longer duration.

Question 29

Why are there sex differences in pain perception?

Answer 29

Biological factors -> Genetic differences -> Sex hormones -> Brain imaging. Psychosocial factors -> Negative emotion -> Coping strategies -> Social influences

Question 30

Sex differences in opiodergic mechanisms

Answer 30

Differential sensitivity to morphine in males and females (to get same pain relief) - females tend to be more sensitive (need less morphine) Mu opioid receptor activity -> females may show less endogenous analgesic effects -> differential distribution and activation of receptors in male/females. Kappa opioid receptor agonists have stronger analgesic effects in females -> mediated by melanocortin-1 receptor (Mc1r) (also involved in regulating skin and hair colour) -> Women with the Mc1r2 allele (associated with red hair and fair skin) display greater analgesic response than men with same allele or females with other variants. Need for: Sex specific treatments, Pharmacogenetics, Other descending control mechanisms.