pain

Pain receptors

Nociceptors

The free nerve endings are the end of the nociceptors

free nerve endings across the skin

when skin is damaged as part of inflammatory response body will make prostaglandins

Prostaglandins

Prostaglandins are hormone-like substances that play a significant role in pain and inflammation. They are involved in the body's natural healing process, but excessive production can lead to chronic pain and inflammation.

responsible for vasodilatation so make the area red and also sensitise the free nerve endings making it more likely that the free nerve endigns will send infor to cns

free nerve endings respond to pain and prosotoglanding sensitise more

types of Nociceptors

• Highly myelinated axons (Aδ fibres)

• Unmyelinated axons (C fibres)

• Highly myelinated axons (Aδ fibres)

convey mechanical pain very quickly and precisely: early pain

• This is informative about the location

something happened and where

• Unmyelinated axons (C fibres)

convey different kinds of pain more slowly and less precisely: late pain

• This is vague about location (wider splits, so can tell pain but don’t know where)

respond to mechanical damage, as well as other things such as heat

A delta will become c ie dull becomes

what naturally contains capsaicin

chillis

some receptors for hot pain and hot feelings

when are we aware of pain

when it reaches the brain in the somatosensory cortex where we percieve it as pain

the descending analgesia circuit reduces pain by

inhibiting the pain signal from entering the central nervous system at the first synapse

Types of Nociceptors

• Sensitive to extremes of mechanical stimulation • Sensitive to pungent irritants (e.g. mustard oil, etc) • Sensitive to extremes of temperature, acid and capsaicin the other 2 are due to the c

Somatosensory Pathways of pain

substance p

info from nociceptor from dorsal route ganglion comes in and makes a synapse on the dorsal horn neurone in the spinal cord

this dorsal horn has a really long axon that first of all crosses midline pf spinal cord then runs all the way to the thalamus in the brain and makes a synapse

the thalamic neurons then make synapses into the primary somatic sensory cortex wheres theres a map of our body to tell us where the pain is

in addition to glutamate that synpapse also uses substanc ep as a co transmitter and when substance p is released the signal is much stronger

Pain Perception “pain in the brain”

• Can be independent of input (Phantom Limb) (not caused by free nerve endings but representation of the area still fires an action potential)

• Dual (at least) brain mechanism:

pain is atleast 2 things ie there is pain and is here ie ss cortex aswell as the unpleasentness feeling of pain ie emtoion that attatche to antierior cingualte

• Pain Sensation (physical)  Primary SS Cortex

• Immediate Unpleasantness perception  Anterior Cingulate Cortex

just the rep of pain wouldnt bother us

Pain Sensation (physical)

Primary SS Cortex

• Immediate Unpleasantness perception

Anterior Cingulate Cortex

Pain Perception Hypnosis-Induced Analgesia

study in which pain was induced experimentally by putting hand in 47 degree water to induce pain

scan brain to look at 2 areas p SSC and ac

increased activity in SSC and AC in one group

in another group did pain induction and hypnosis to allow people to tolerate pain better then scanned brain, in this group there was no difference in the activation of primary somatosensory cortex but a much lower response in anterior cingulate cortex therefore acc is responsible for unpleasantness of pain but primary somatorsensory cortex is the mapping ie many aspects

Pain suppression

• Non-drug approaches • Capsaicin • NSAIDS • Paracetamol • Opiates • Cannabis

Descending Analgesia Circuit

located in the brain stem

begins in PAG, which is normally not active/ the inhibitory interneurons in the PAG keep the projection neurons from firing action potentials so nothing comes out

When activated action potentials run down those axons to the Raffi Magnus

the raffi Magnus then activates inhibitory interneurons in the spinal cord and dorsal horn, and they inhibit both the spinal cord neuron as well as the incoming signals from the presynaptic termianl from the nociceptor

so the descending circuit stops the start at the first synapse from releasing glutamate and substance p to begin with but if some comes through it stops the neuron that recieves it from firign action potentials

so dotn feel pain

Pain Suppression: via the descending circuit

Non-drug approaches

• Direct stimulation of the PAG (suppresses pain signals to activate DAC)

• Stressful situations: soldiers, athletes,... (adrenaline doesn’t suppress pain but adrenaline and stress response are both linked to stress not causal)

• Placebo effect- non-active substance that you are told has an effect.

Pain Suppression: Non-drug approaches - Placebo

Placebo skin cream leads to activation of dorsolateral prefrontal cortex

• This in turn activates the Peri-Aqueductal Grey Matter

• Activation of DAC Wagner et al. (Science 2004)

Given skin cream they told would reduce pain when scanning brain see activation in the lateral prefrontal cortex which is one area that controls the stress response and activates the PAG in the midbrain so people felt less pain due to PAG activation.

Pain Suppression: Non-drug approaches

• Direct stimulation of the PAG • Stressful situations: soldiers, athletes,... • Placebo effect • Acupuncture Tested using Naloxone, an opiate receptor blocker (acupuncture works on other animals aswell by triggering DAC if stimulated with currents can have same effect)

Pain Suppression: Capsaicin

• Used topically on the skin for muscle pain (feels hot)

• Depletes sensory neuron terminals of Substance P, providing local analgesia

riggers pain response that would detect pain that released substance p and glutamate, depleting these 2, so no more substance P can be released

briefly overstimulating the neurons to pain

this is only topical to area

Pain Suppression: NSAIDs

= Non-Steroidal Anti-Inflammatory Drugs: E.g.: Aspirin Ibuprofen COX-2 inhibitors Act peripherally as cant cross bb barrier wont help inflammation in the brain as can bind to carreirs but can unbind

(poor blood-brain-barrier penetration because of binding proteins in the blood)

what does NSAIDs stand for

= Non-Steroidal Anti-Inflammatory Drugs

Pain Suppression: NSAIDs

Mechanism of action:

Inhibition of Cyclo-Oxygenase 1 and 2 (COX-1 and COX-2) → Reduction of the production of prostaglandins which are the signalling for inflamation, they also sensitise the nerve endings so less of this less pain reduce inflammation and pain

Location of NSAID action pain

Prostaglandins

NSAIDs work by inhibiting the synthesis of prostaglandins, which are involved in pain and inflammation, primarily at the peripheral site of inflammation, but also at the central nervous system. This inhibition is achieved by blocking the cyclooxygenase (COX) enzymes, which are responsible for prostaglandin production.

Pain Suppression: NSAIDs side effects

• COX-1 involved in blood clotting: aspirin prevents blood clotting. clotting not enough bad for oyu

• COX-1 involved in protection of stomach lining from acid: NSAIDs bad for stomach, stomach attacked by acid so cox1 helps prevents it

Pain Suppression: Paracetamol

• Mechanism still under investigation, but:

One hypothesis is that its an agonist to the CB1 receptors

Paracetamol itself is not a very active molecule, but is turned into am404 and binds to cannabinoid receptors

• Paracetamol reacts with endogenous molecules to form AM404, an agonist of the TRPV1 and CB-1 cannabinoid receptors

• TRPV1 channels are found on nociceptors

if you get a cb1 antagonist parecetomal doenst work

Pain Suppression: Opiates

• Derived from the opium poppy or synthetic

used for pain for thousands of years

• Long-time used and very powerful analgesics

• Well-known for their abuse-potential

• CB-1 receptors are found in many central and peripheral pain-related circuits, including the Descending Analgesia Circuit, where they reduce inhibition.

9opiate drugs opioid in body)

Opiates • Taken in different forms:

• Opium: mostly smoked or eaten

• Morphine: many different ways; only 20% crosses blood-brain barrier (half- life: 3-4h) • Codeine: typically oral, as cough suppressant

• Heroin (=diamorphine): typically injected; lipid soluble, so more crosses the blood-brain barrier; cleared quickly (half-life 0.1-0.25h)

• Oxycodone (OxyContin): pills with either fast (15min on empty stomach) or slow uptake (half-life: 4.5h) • Fentanyl: highly powerful synthetic opiate (highly lipophilic; half-life 3-7h)

Opiates Short Term effects

• Most opiate drugs share these characteristics: • Relieve pain • Relieve cough • Relieve diarrhoea • Induce hypothermia • Induce sleep as body temp drops • Stimulate pleasure makes you feel good (endogenous systems responsible for pleasure so triggers pelasure)

if you take to much you suppress your breathing so addicts may fall asleep and stop breathing

Opiates: Physiological Action

• Opiate drugs mimic the action of endogenous opioids: endorphins

• They bind to endogenous opioid receptors, which can be found in many places in the body and the brain

endogenous opioids:

endorphins

Opioid Receptors

• Discovered in 1973 (Pert and Snyder)

• 3 major sub-types: delta, kappa and mu slightly diff functions around the brain

• Are present in the brain, for example: • Preoptic area (hypothermia) • Mesencephalic Reticular Formation (sedation) • Locus Coeruleus (sedation) • Ventral Tegmental Area and N. Accumbens (rewarding) • Peri-Aqueductal Grey area (pain relief, pleasure) • Brainstem (coughing centre, breathing regulation)

And in the periphery (diarrhoea relief)

Descending Analgesia Circuit opiates

activate and mimic

Opiates: Long-Term effects

• Surprisingly mild, as long as the drug is taken: • Constipation • Pupil constriction • Menstrual irregularity • Reduced libido • BUT: withdrawal symptoms!

Heroin Withdrawal Effects

• Begin 6-12 hours after last dose and disappear after 7 days or so

• Include: • restlessness – runny nose • watering eyes – sweating • chills, shivering – gooseflesh • nausea, vomiting – diarrhoea • tremor – muscle spasms

Counteracting Withdrawal Effects herion

• More Heroin • Methadone • Acupuncture (or modern equivalent) • Avoid drug-related contexts

Opiate Addictiveness:

Mesotelencephalic Dopamine System

• In Ventral Tegmental Area (VTA): • Opiates inhibit GABA-ergic interneurons

• This releases inhibition from neurons which project to Nucleus Accumbens • More dopamine release

• In Nucleus Accumbens: effects independent from but similar to Dopamine from VTA

Opiates Legal Status

• CLASS A: • Illegal to possess (except by prescription) • Illegal to sell (except by pharmacists) • Illegal to give away (except by prescription) • Possession: up to 7 years + unlimited fine • Dealing: up to Life + unlimited fine • Codeine is Class B

Cannabis intake

• Smoked (as joints or in a pipe, often mixed with tobacco) or eaten (often in baked goods) • Different parts of the plant used: resin (hash), leaves (grass/weed) • 20-50% of active compounds (THC & CBD) is taken up from smoke, less from ingested (6%) • THC and CBD are very lipid soluble and easily crosses the blood-brain barrier • They are easily stored in fat tissue, and has a half- life of 7 days (still detectable after 30 days)

Cannabis Short Term effects • Recreational use:

• Reduction in anxiety • Dissociation of ideas • Heightened sensation • Distorted sense of time (seems slower) • Intense emotional experiences

hallucinations (infrequent)

Cannabis Short Term effects (2) • Medicinal use:

• Reduces nausea • Increase in appetite (munchies) • Dilation of bronchioles • Blocks seizures • Decreases severity of glaucoma

-Reduces pain • As effective as opiates for acute pain • Greater potency and efficacy than opiates for chronic pain (but side effects)

• Sites of action include: • Peripheral nerves • Direct spinal cord activity • Descending analgesia circuit • Anterior Cingulate Cortex

negative side effects of cannabis recreationally Cannabis Short Term effects (

• Intoxication similar to alcohol: • Uncoordinated motor performance • Slower reflexes (even 24h later!!) • Attention and short-term memory problems (very distractable) • Panic Attacks • Paranoia • No realistic lethal overdose (equivalent to 7kg of THC)

Cannabis Physiological Action

• Δ9-tetrahydrocannabinol (THC) • Partial agonist on CB1 and CB2 receptors • Mainly responsible for psychedelic effects, but also many of the others

• Cannabidiol (CBD) • Antagonist on CB1 receptors • Interacts with many other receptors in the brain • Very complex and not well understood yet

Endocannabinoids

why do we have cannibis receptors? for endogenous cannibis

• Endogenous ligands of cannabinoid receptors are anandamide and 2-AG • The highest concentration of cannabinoid receptors exists in the hippocampus (memory)

Function of Endocannabinoids

they are released in reverse

• Released from POST-synaptic side of a stimulated synapse • Work in the close vicinity on other synapses

• Suppresses the PRE-synaptic release of neurotransmitters

• In the hippocampus, this affects GABA, hence suppressing inhibition: Depolarization-induced Suppression of Inhibition (DSI)

lipids

Depolarization-induced Suppression of Inhibition

Gaba-ergic neuron Endogenous cannabinoids released from post-synaptic terminal Cannabinoid receptors on presynaptic terminal

Distribution of Cannabinoid Receptors

• Cerebral Cortex (psycho-active effects) • Hippocampus (memory effects) • Movement control centres (motor dysfunction) • Brain stem (analgesia, vomiting control, sleep) • Spinal cord (analgesia) • Hypothalamus (appetite, sleep) • Amygdala (emotions) • ...

Case study • 66-year-old female

Requires no post-surgical analgesia

• Regularly burns herself on her stove without noticing (except when she smells her flesh burning).

• Defect in the FAAH enzyme (breaks down anandamide) which breaks down endogenous cannaboids so had very high levels of it

• Very high blood levels of anandamide (but not 2-AG, which is not broken down by FAAH).

Cannabis Long-term effects

• Problems associated with smoking (not related to THC)

• Impairments in memory recall

• Impairments in attention

• Slower decision making

• Increased odds of psychosis by up to 5x with high potency versions (skunk) skunk causes a lot more psychosis

• Decline in IQ with persistent use (from age 13-38)

• Especially vulnerable if starting during adolescence

cannabis long term iq effects

study in new zealand looked at lots of things and drug use

never used used not dependent dependent

showed the more often people used cannibis had drops in iq 1 point

Cannabis Addictiveness

Physical dependence:

• Tolerance develops during extended use, but withdrawal symptoms are rare

• Long-term users may experience sensitization of the desired effects

slow clearing allows body to readjust to the withdraw

Cannabis Addictiveness Psychological dependence:

• THC acts directly on the N. Accumbens to increase dopamine release from VTA terminals

• Yet people typically smoked only occasionally and could drop the habit fairly easily

• More recent versions (e.g. “skunk”) however have higher levels of addiction

little evidence that its actually addictive but high thc and spice can work very differently

Cannabis Legal Status

• CLASS B:

• Illegal to possess

• Illegal to sell

• Illegal to give away

• Possession: up to 5 years + unlimited fine

• Dealing: up to 14 years + unlimited fine

• Driving under influence: heavy consequences

Descending Analgesia Circuit summary

a pain modulation pathway in the central nervous system that reduces pain signals by inhibiting nociceptive transmission. It starts in the periaqueductal gray (PAG) in the midbrain, relays to the rostral ventromedial medulla (RVM), and then projects down the spinal cord to modulate pain at the dorsal horn. This pathway is crucial for endogenous and exogenous opioid-induced analgesia, and plays a role in pain chronification and the development of tolerance to opioid

PAG (Periaqueductal Gray):

The PAG receives pain information and processes it, sending signals to the RV

RVM (Rostral Ventromedial Medulla):

The RVM integrates "top-down" (from the PAG) and "bottom-up" (from the spinal cord) inputs, regulating RVM cell types that either suppress or facilitate pain. RVM neurons are functionally classified as "OFF-cells" (which suppress pain) and "ON-cells" (which facilitate pain)

Descending Pathways:

The RVM projects down the spinal cord, releasing neurotransmitters like serotonin and norepinephrine to inhibit pain signals in the dorsal horn.

endogenous Opioid System:

The descending pathway can activate the endogenous opioid system to suppress pain at the dorsal horn, presynaptically, and on first-order neurons.

GABA Disinhibition:

• Opioids and cannabinoids are believed to activate descending analgesia through "GABA disinhibition," where they suppress inhibitory GABAergic inputs onto output neurons in the descending analgesic pathway.

Stress-Induced Analgesia:

The descending PAG-RVM system is involved in stress-induced analgesia, a phenomenon where pain perception is reduced in resp

whats the Descending Analgesia Circuit

Descending pathways play a critical role in the central modulation of pain. A particular descending PAG–RVM pathway mediates the phenomenon of stress-induced analgesia. Opioids and cannabinoids are proposed to activate this system via a process of GABA disinhibition.

how do we know all pain suppression non-drug approaches are caused by DAC

-when you give people naloxone which is a opiate blocker

the approaches don’t work on stress acupunture or placebo

as antagonist of opiate receptors and part of this is the release of encephorlin in sc and endogenous opiates in PAG

if you block this effect can tell that something is activating the DAC.

ACTION POTEINAL ROUTE WHEN STUB TOE

nocicipetors have free nerve endings which detect sensations this casues pressure gated na channels to open so poteinal increases depolaising once threshold met voltage gated sodium cahnnels open

cell body in dorsal route ganglion near spinal cord

makes synapses in the cross section of the spinal cord in dorsal route ganglion where nerve endigns come in (dorsal in sensory infor ventral out mechaniscal)

the action poteinal the reaseches the psot synaptic termianl and memebrane poteinal depoalriese there due to ap

this triggeres release of nt due to volatge gated chlorine channels which act as a messeenger mol

cl2- bind to vesicles causes shape change so nt are released

this causes release of glutamtae and substance p across cleft which then binds to ligand gated channels and na+ moves inwards this triggers action poteinals all the wat ti the brain triggering feeligns of pain

if there is damge in the perephery but sc damage no pain

higher threshold for substance p release than

glutamte

most common nt

periphery- acetylcholine

cns (excitatory)- glutamate

how does the dac inreact wih opiates wok summary

opiates inhibit activity inhibioty neurons thus removing inhibition neuron that communicate with nuclus raphe magnus

nuclus in raphe magnus in medulla

in the dorsal horn of sc the interneurons inhibit neuron that transmits pain to the brain and the axon towards nociceptrs also has encepholin receptors

opiates work the same as endogenous opiates by inhibiting inhibitory interneurons in the PAG

opiates also bind to enchepholin receptors so stop pain in put

cannibis areas of action

• Sites of action include:

• Peripheral nerves

• Direct spinal cord activity

• Descending analgesia circuit

• Anterior Cingulate Cortex

why does cannibis take so long to clear

Like all cannabinoids, THC is fat-soluble, meaning it can hang around in your body’s fat tissue for weeks, especially following frequent use, before it’s processed by the liver and excreted in the urine. Occasional users may clear THC within 3 to 5 days, while chronic users can retain it for 30 days or more. The duration of THC in your system is affected by factors such as frequency of use, body fat, metabolism, the potency of the cannabis, and liver function.

depolarisation-induced suppression of inhibition summary ENDOGENOUS CANNABOIDS IN HIPPOCAMPUS

Depolarization-Induced Suppression of Inhibition (DSI) is a short-term form of synaptic plasticity in the brain, especially prominent in the hippocampus. It involves a temporary reduction in inhibitory GABAergic neurotransmission following a strong depolarization of a postsynaptic neuron.

depolarisation-induced suppression of inhibition summary ENDOGENOUS CANNABOIDS IN HIPPOCAMPUS MECHANISM

• Postsynaptic depolarization leads to a rise in intracellular calcium.

• This triggers the production and release of endocannabinoids (eCBs)—mainly 2-arachidonoylglycerol (2-AG).

• These eCBs act retrogradely by diffusing back across the synapse.

• They bind to CB1 cannabinoid receptors located on the presynaptic terminals of GABAergic interneurons.

• CB1 activation inhibits GABA release, temporarily reducing inhibition onto the postsynaptic neuron.

• The result is a brief window of disinhibition, enhancing the excitability of the postsynaptic cell.

HOW DOES CANNIBIS ALTER DIS system

1. THC Mimics Endocannabinoids

• THC is a plant-derived cannabinoid that mimics endogenous cannabinoids like 2-AG and anandamide.

• It binds to CB1 receptors in the brain, including those in the hippocampus.

2. Disrupts Normal DSI Regulation

• When THC binds to presynaptic CB1 receptors, it inhibits GABA release—just like endocannabinoids during DSI.

• However, THC is not tightly regulated like natural endocannabinoids.

• This leads to prolonged suppression of inhibition, not the short, activity-dependent DSI seen normally.

3. Effects on Hippocampal Function

• Chronic or high-dose THC can disrupt the fine balance of excitation and inhibition in the hippocampus.

• This impairs synaptic plasticity, particularly long-term potentiation (LTP), which is critical for learning and memory.

• THC use is associated with short-term memory deficits, likely due to this dysregulation of inhibitory control.

if the pre-synaptic terminal were the glutamatergic primary pain afferent (towards cns) (efferent is away)in the action of endogenous cannaboids this would lead to…

from periphery to spinal cord then ths would stop release of neurotansmitters so therefore would decrease pain as stops gluatamte release

what analgesics work in the CNS

OPIATES

CANNAVVOIDS

PARACETAMOL