L14: Pain Flashcards
What is pain?
- a unique, unpleasant sensory or emotional experience associated with tissue damage
What are the two aspects of pain?
Sensory aspect: sensory discriminative, involves threshold intensity and location of pain
Emotional aspect: affective motivational, relates to the emotional experience of pain as unpleasant, threatening, or aversive
What is the basic pain processing pathway?
- Descending brain pathways from the cortex and limbic brain to the midbrain and spinal cord.
- NTs released to modify the perception of pain and its intensity
How does pain perception occur?
- Pain perception occurs through a dialogue between ascending & descending pathways
What is nociception?
- nociception = neural process of encoding noxious stimuli,
- which includes sensitivity to a noxious tissue-damaging stimulus/stimulus that may become noxious if prolonged.
What are the four physiological processes involved in pain?
Transduction
Transmission
Modulation
Perception
Describe the four physiological processes involved in pain
- Transduction: Nociceptors respond to tissue-damaging stimuli (mechanical, chemical, and thermal) & transmit the signal to CNS
- Transmission: Nociceptive signals are carried from site of tissue injury to brain regions involved in pain perception (involving primary & secondary pain transmission neurons)
- Modulation: Descending pain modulatory system alters activity in the spinal cord through monoaminergic NTs, resulting in inhibitory/excitatory effects.
- Perception: Pain perception occurs in the brain regions ncl. the cortex, thalamus & limbic brain.
What are some endogenous inhibitors involved in the modulation of pain?
- GABA: mediates pain modulation through GABA interneurons & descending inhibitory pathways.
- Opioids: Endogenous opioids e.g. enkephalins, beta-endorphins, and dynorphin act as pain modulators.
- Noradrenaline (NA): Mediates pain modulation via descending inhibitory pathways originating from the Locus Coeruleus.
- Serotonin (5HT): Acts as a pain modulator through descending inhibitory pathways originating from the Raphe Nucleus
What are the characteristics of acute pain?
- Associated with tissue damage
- Has an evolutionary advantage
- Self-limited and doesn’t last more than 12 weeks
What are the characteristics of chronic pain?
- It is a disease state
- Outlasts the normal time of healing
- No evolutionary advantage
- Includes conditions like neuropathic pain, chronic migraines, and fibromyalgia
- Results in a negative impact on the quality of life
What is peripheral sensitization?
an increased sensitivity to afferent nerve stimulation
What are the effects of peripheral sensitization on pain response?
- increased pain response due to production of neuropeptides like substance P and histamine by nociceptors
- leads to primary hyperalgesia & allodynia
- also involves the upregulation of existing and new receptors.
what is hyperalgesia and allodynia
- hyperalgesia = heightened pain response to painful stimuli
- allodynia = pain response to non-painful stimuli
How does peripheral sensitization contribute to chronic pain?
- causes a ↓ threshold of firing & ↑ responsiveness of nerve endings, including C-fibers (which respond to heat, pressure, and impact stimuli)
- activated & sensitized by locally produced inflammatory mediators like bradykinin, histamine, prostaglandins, leukotrienes, Ach, 5HT, and substance P
- these inflammatory mediators ↓ the threshold for activation of nociceptors, contributing to chronic pain
What is central sensitization?
- amplification of pain by CNS mechanisms, representing altered function of nociceptors.
-triggered by peripheral injury or increased nociceptive input
How is central sensitization manifested in the central nervous system?
3 ways:
1.↓ in the threshold for activation of neurons, making them more easily excitable.
2. ↑ in receptive field size and recruitment of novel input, making neurons more likely to fire.
3. ↑ in spontaneous background activity of neurons
What are the consequences of central sensitization?
- input from low-threshold, non-nociceptive fibers activates nociceptive-specific neurons
- Activates nociceptive pathways
- can lead to clinical pain characterized by allodynia & hyperalgesia & spontaneous pain
What are the types of pain?
- Nociceptive Pain - Arises from tissue damage and inflammation
- Neuropathic Pain - Arises from damage to nerve fibers
- Other Pain - Arises from neurological dysfunction in the CNS
What are the mechanisms in inflammation related to pain?
- PGE2 (Prostaglandin E2) and PGI2 (Prostacyclin) are important pain-producing or enhancing mediators.
- Considered enhancers of pain perception.
How does nerve laceration contribute to pain?
- Surgical trauma can cause nerve laceration, leading to neuropathic pain.
- Neuropathic pain is difficult to treat with analgesics
How are inflammatory pain and neuropathic pain treated differently?
- Inflammatory Pain: Preferably treated at the source, where inflammatory mediators are being released.
- Neuropathic Pain: Usually arises due to changes in the spinal cord and CNS. Treating at the source may not be effective
What makes neuropathic pain challenging to treat?
- Nerves take longer to recover from damage
- making neuropathic pain often chronic & difficult to treat with analgesic medications
What are the coreleased neurotransmitters in certain pain pathways?
- Substance P and glutamate are coreleased.
- Substance P activates NK1 receptors, which prolongs the activity of glutamate in pain transmission
How do NSAIDs work as pain relievers?
- NSAIDs inhibit COX enzymes, preventing the production of prostaglandins
- COX-2 is expressed in inflammation, and by blocking it, NSAIDs reduce pain and inflammation
What is the mechanism of action of paracetamol as a pain reliever?
- mild analgesic that lacks anti-inflammatory effects.
- exact mechanism of action unclear
- it weakly inhibits the synthesis of prostaglandins
What happens to ion channels in neuropathy, and how does it contribute to pain?
- ion channels behave abnormally, leading to the unnecessary transmission of electrical impulses
- Na+ channels can accumulate at the site of injury and seem to be found only in the CNS
- contributes to the development of neuropathic pain
What are the different types of nerve fibers?
Aδ fibers
C fibers
Aß fibers
describe Aδ fibers
- thinly myelinated
- transmit info rapidly at around 15m/s, and are responsible for sharp and intense pain perception
- cell bodies located in the dorsal root ganglion.
describe C fibers
- non-myelinated
- transmit info at slower rate of around 1m/s, & responsible for dull and throbbing pain perception
- cell bodies located in the dorsal root ganglion.
describe Aß fibers?
- heavily myelinated
- small diameter
- fast-conducting fibers that are activated by non-noxious stimuli e.g. pressure & touch
Why are secondary messengers necessary for the response to extracellular chemical signals?
- because they amplify cellular responses
- act as intermediaries between cell surface receptors & intracellular processes - allowing a single extracellular signal to trigger multiple intracellular responses
How do secondary messengers amplify cellular responses to extracellular signals? Provide examples.
- amplify cellular responses by propagating and amplifying the initial signal
- can activate multiple intracellular pathways and regulate various cellular processes
- EXAMPLES: cAMP, IP3/DAG, and Ca2+ ( which activate various kinases, enzymes & TFs to mediate cellular responses to single extracellular signal)
What is the normal role of glutamate at synapses, and how does it contribute to neurodegeneration in disease?
- major excitatory neurotransmitter in the brain
- important in synaptic transmission & plasticity (learning & memory)
- excessive glutamate release and receptor activation can lead to excitotoxicity (contributing to neurodegeneration in diseases e.g. PD & AD)
