Module 9: Analgesics (1) - Pain Pathways

Somatosensation

• The sense of touch, pressure, and vibration against the skin. – tactile information that is relayed to the brain to allow for appropriate motor actions

  • e.g. “Am I holding this egg properly?”.

Proprioception

• A sense of where body parts are (joints, angles, length of muscles).  – a subcomponent of Somatosensation that allows for the correct output for movement – sensory neurons detect these components – does not require a conscious effort

  • e.g. “Is my leg straight or bent at the knee?”.

Nociception

• The neural processes of encoding and processing noxious (pain-causing) stimuli

• It can combine information from the internal state and integreate information from external sitation to affect our perception of pain

• Sensory neurons relay signals when tissue damage occurs, encoding the stimulus into an action potential, which sends a neural code to the brain.

• It is the sensory input that leads to pain, but it distinguishes between the objective neural process and the subjective experience of pain.

  • this signal/ neural input is thesame across individuals

Pain

• A perception produced in the brain due to nociceptive singals from the periphery tothe spinal cord and the brain

• It is not a sensory input, but an unpleasant sensory and emotional experience associated with actual/potential tissue damage.

  • subjective experience

Nociceptive Signal Transmission and Modulation

• C-fibres and other fibres transmit signals from skin/nerve endings to the dorsal root ganglion (cell bodies located here).

  • These fibres synapse at different layers/laminae of the dorsal horn in the spinal cord.

• Ascending Pathway: After processing and encoding, the nociceptive signal is sent to the brain, mediated by various neurotransmitters.

• Descending Pathway: The signal will be and will be integrated with other information that has been integrated by the brain →, demonstrating top-down control of pain.

Noceceptors

• They encode noxious stimuli (e.g., burn, bee sting, broken limb) as neural information in the form of action potentials(APs), which are sent to the brain.

• Action potentials from all sensory modalities look the same, but the brain interprets them based on their pathways to understand their meaning, such as pain.

• The brain processes these signals and adds meaning, recognising them as potentially harmful or noxious based on their strength.

  • The signal will persist if the stimulus is noxious but dissipate if it is not.

Sensory Noiceceptor Inputs

• Inputs that are perceived as painful or dangerous help us avoid future harm by protecting us from injury.

Factors Affecting The Extent of Pain

• Strength of stimulus – n.o and strength of Aps

• Internal state (why?).

Effect of the Internal State on the Perception of Pain

• Pain is a perception that originates within the CNS and cannot be sensed externally.

• Nociceptive information combines with internal states (such as attention and arousal), which can alter how pain is perceived.

• Pain perception occurs in higher brain centres, where the brain modifies incoming sensory signals based on the internal state (e.g., distractions might reduce the perceived intensity of pain).

• Pain is also influenced by the integration of sensory nociceptive signals with the internal state, allowing for altered perceptions (e.g., ignoring pain if distracted).

• This means the same nociceptive stimulus can be perceived differently depending on internal conditions (such as stress, focus, or mood).

Effect of External State of Perception of Pain

• environmental factors or events, for e.g., can influence the perception of pain.

• Emotional connections such as arousal and attention can significantly modulate how pain is perceived.

• Pain perception involves both central (CNS-based) and peripheral elements, leading to a final perception of pain that integrates both sensory signals and contextual factors (emotional, environmental, etc.).

• This means pain perception can change depending on external circumstances, like how the context of the situation can make the same level of pain feel more or less intense.

Types of Nociceptors

• These afferent fibres send information from e.g. the skin or site of detection down and through the spinal cord and to the brain

• There are several different types

  • thermal

  • mechanical

  • polymodal

  • silent

Types of Nociceptors: Thermal

• Sense noxious hot and cold temperatures

  • Hot/cold (>45°C or <10-15°C becomes ‘pain’) – turns from an ambient temperature, which still must be sensed) into a noxious sensation which is then perceived as pain

Types of Nociceptors: Mechanical

• Sense squeezing, stretching, penetrating skin (sharp, intense pain, e.g. transmitted via Aδ fibres).

  • A delta fibre is myelinated - fast transmission – signal jumps between nodes

Types of Noicieption: Polymodal

• C-fibres (unmyelinated – slower mode of transmission)

  • Sense dull, diffuse, burning pain.

Types of Nociception: Silent

• Visceral swelling/distension (intense, poorly localised pain as we don’t need to know exact location).

  • Detect changes in the visceral organs

Mechanical Nociception: Strong Pressure From a Blunt Probe or Object

• No response – not a noxious stimulus

• recording from an afferent Aδ fibre (Sensory receptor) shows no response following mechanical stimulation via blunt object - not noxious won’t damage skin

Mechanical Nociception: Sharp Pin Prick

• Equal pressure over a small area gives a robust response. – more likely to produce tissue damage

  • Robust response – rapid onset, with lots of AP firing for the duration of the force applied

Mechanical Response: Pinching with Serrated Forceptrs

• Stronger responses due to damage in a larger area

  • Stimulus much more likely to produce tissue damage – strong volley output from A Delta fibre

  • The n.o AP fired is proportional to the amount of potential damage that could occur

Thermal Nociception

• Heat-sensing Aδ fibres (myelinated, fast) and some C fibres express TRP channels (Transient Receptor Potential channels).

• TRPs detect either low or high threshold temperatures - have a magnitude of activation:

  • Cold: TRPM8, TRPA1

  • Heat: TRPM3, TRPV3, TRPV1

  • Ambient: TRPV4 (not nociceptive, more somatosensory)

• TRP channels act as nociceptive sensors when activated at noxious temperature thresholds.

TRP Channel Sensitivity to Natural Compounds

• TRPA1: Activated by garlic, radishes, cinnamon

• TRPM8: Activated by menthol (mint)

• TRPV1: Activated by capsaicin (chili) and ethanol

• TRPV2: Responds to THC and endogenous cannabinoids

• These channels allow nociceptors to detect chemical stimuli as well as thermal changes.

Nociception Activation Via the Central Pathway

• Tissue damage occurs (e.g. mechanical/physical rupture).

  • Primary afferent neurons with nociceptors at nerve endings transmits the signal down the axon to its cell body located in the DRG where it synapses with 2nd order neurons to then transmit the signal to the brain, where pain is perceived

• This causes a local release of Inflammatory mediators (e.g. bradykinin, 5-HT, histamine, prostaglandins, ATP, H⁺).

• Nociceptors (Aδ fibres) are activated and encode the signal into an action potential

• The action potential travels along the primary afferent neuron, through the dorsal root ganglion (DRG).

• The neuron synapses in the dorsal horn of the spinal cord with a second-order neuron.

• The signal ascends to the brain, where it is integrated with other sensory inputs to allow for the perception of pain.

Nociceptive Activation - Positive Feedback

• This allows for the potentiation of the central pathway, inflammation and a more widespread response

• 1. Activated Aδ fibre may have branch points which propagate the AP, allowing it to spread along the axon.

• 2. Branch points can terminate locally in tissues allowing the release release of substance P (SP) (neuropeptide Y – involved in pain sensation), or CGRP. (calcitonin)

• 3. Substance P stimulates granular immune cells (mast cells, neutrophils) to degranulate and release histamine (drives inflammation and activation of Aδ fibres and vasodilation etc).

  • Potentiation of A delta fibre

• 4. CGRP and substance P dilate local peripheral blood vessels – allowing for increased blood flow and for immune cells to enter and potentiate this inflammation

  • These loops stimulate inflammation and then stimulate the activation of immune cells which results in further activation of substances

  • These substances will then begin to diffuse out of this local area giving rise to inflammation and the pain spreading away from the local tissue area

Neurogenic Inflammation

• Local inflammation at the tissue level

• Spreads through mediators (e.g. histamine).

• Prostaglandins are produced by COX enzymes.

• Spread of the initial site of damage → the spread of nociceptive signal around initial local site

  • Flaring site where there are ‘concentric circles of pain’ perception that spreads out from the initial site

Mechanical Hyperalgesia

• Sensitivity of the skin around the initial area of injury is higher → more painful the closer to the wound you get, but not where the wound is.

• Acts as a protective mechanism – makes the regions more sensitive so that we are more cautious and don’t expose it to further damage

Example of Mechanical Hypergesia

• After a burn the threshold for the burn at a series of sites where the damage was and proximal to damage the threshold for pain decreases → less stimulus is required for that area to feel pain

  • Change from local to neurogenic inflammation = greater pain felt

Neurotransmitters Involved in Pain Neurotransmission

• Glutamate - Major excitatory neurotransmitter

• Substance P

  • they are co-released from vesicles of the DRG cells (e.g. in the C-Fibre) onto second-order neurons of the spinal cord

Substance P in Pain Neurotransmission

• It induces slow depolarisation that prolongs glutamate’s excitatory effects.

• Not rapidly broken down – acts via paracrine signalling, lingering on nearby target cells.

• Can laterally diffuse, activating nearby synapses, even from different sensory origins.

  • This can cause multiple synapses (from different nociceptors) to converge on the same second-order neuron.

  • As a result, pain becomes harder to localise, since the brain only detects activation of the second-order afferent neuron, not its exact source.

• Pathological states may cause its upregulation, increasing its release and potentially contributing to abnormal pain processing (e.g. chronic pain, hyperalgesia).

C-Fibre Wind-UP

• Repetitive activation of C-fibres (not Aδ fibres) leads to increased excitability of second-order spinal neurons.

• This results in temporal summation – where repeated stimuli cause a progressive increase in pain perception, even though the stimulus intensity remains the same.

• The firing rate of the secondary neruons can increase in response to the same nociceptive input, sensitising these spinal cells due to the repetitive activation of the C-fibre

Mechanism of C-Fibre Wind-UP

• 1. Stimulus (S) is applied repeatedly to the skin.

• 2. This activates Aδ fibres (fast, myelinated) and C-fibres (slow, unmyelinated), which synapse on second-order neurons in the spinal cord.

• 3. Electrode recording tracks action potentials from the second-order neuron during each stimulus (1–17).

  • Aδ fibres are mentioned - AP reaches 2nd order quickly; C-fibres are unmyelinated - takes longer

• 4. The A-volley (Aδ input) is quick and consistent across stimuli.

• 5. The C-volley (C-fibre input) is slower but gradually increases in spike number with each repetition – even though the stimulus doesn’t get stronger.

• 6. This results in increased excitability of the second-order neuron – a phenomenon known as "wind-up".

  • a subsequent increase in afferent response and no change to A fibre, causing an increase in the excitability of the 2nd order neuron

• This mechnaism contributes to enhanced pain perception due to repeated stimulation and is a key mechanism in the temporal summation of pain.

C-Fibfre Wind-UP: Aδ or Aβ fibres

• Fibres release glutamine

• This results in a small depolarisation through the AMP receptors, resulting in an Na+ influx (NMDA receptors have Mg2+ block)

• Glu activates postsynaptic AMPA (lots; fast depolarisation) and some NMDA receptors.

• NMDAR are blocked at resting potential by a Mg2+ ion (released only by strong depolarisation)

C-Fibre Wind UP: C-Fibres

• Fibres release Glu and SP

• A signal from these fibres results in an influx of Ca2+ resulting in the release of 2 neurotransmitters

  • Glu activates NMDA receptors

  • Substance P will bind to NK1 receptors, resulting in a much stronger depolarisation which causes the removal of the Mg2+ block and so allows Glu to bind to the NMDA receptors causing Ca2+ entry to the postsynaptic neuron

• Slower response as fibre is unmyelinated but it is longer lasting due to the dual action of these substances – a mechanism thought to modulate pain perception through C-fibre windup

• Increased cytosolic Ca2+ affects other membrane channels, causing an influx of ions into the postsynaptic/second-order neuron, making it much more likely to fir

Congenital Pain Insensitivity

• Occurs in response to autosomal recessive genetic abnormalities that cause an individual to become insensitive to pain

• These disorders result in the loss of physiological and pathological pain sensation

• Individuals can’t detect severe damage such as severe broken bones, often burn themselves by drinking scalding hot drinks and may suffer from accidental self-inflected injuries e.g. biting of the tip of their tongue

Na+ Channel Mutations

• Rare condition (only about 20 cases known) involving mutations in the gene (SCN9A*) that codes for the voltage gated sodium channel NaV1.7.

• People with this condition have an otherwise normal phenotype but are insensitive or indifferent to stimuli that would be painful to other individuals.

• Nav1.7 is important in dorsal root ganglion nociceptive neurons, explaining the mechanism by which the mutations can abolish pain sensation.

FAAH-OUT Mutation

• Congenital pain insensitivity reported in 2019 → involves FAAH-OUT gene which is associated with the endocannabinoid system

• Only found in one individual → mutation led to high levels of anandamide, explaining pain insensitivity

• Identified after a woman had burnt herself several times, but had only noticed due to the smell

  • she also had severe arthritis

Diabetic Neuropathy

• Long-term uncontrolled diabetes can lead to nerve damage (neuropathy) with the legs and feet often the first affected. 

• Damage to sensory neurons initially manifests as pain: the patient will first feel intermittent pain and pins and needles-like sensations (paraesthesia).

• The next stage involves constant pain but in the later stages, pain sensation is lost.

• Coupled with the compromised immune system, poor circulation and poor wound healing, are also consequences of uncontrolled diabetes,

• This lack of pain sensation can mean that diabetics may not detect damage to their feet, resulting in infected wounds that are reluctant to heal.

  • a very common cause of amputations.

Bidirectionality of Pain Pathways

• Neuronal systems and nociceptive signals show bi-directional (up/down) modulation

• They are sent up from the periphery to the brain (ascending) and can be modulated through-down control from the brain back down (descending)

Ascending Pain Pathway

• Nociceptive sensory information is encoded by the sensory afferent neurons that are sent to the spinal cord, where it synapses with the 2^nd order neurons that then pass up to the brain

Nociceptive Information from the Periperphry to the CNS

• Aδ fibres (nociceptive) and Aβ fibres (mechanoreceptive) carry information from the periphery.

• Primary neurons project through the dorsal root ganglion (DRG) (where their cell bodies are located) to the dorsal horn of the spinal cord.

• Aδ and C fibres synapse with 2nd order neurons at different laminae of the spinal cord.

• The signal travels through the spinothalamic tract to the brainstem, thalamus, and brain.

  • major central pathway of the ascending path

• Integration occurs between nociceptive and mechanoreceptive fibres (e.g., Aβ) via interneurons - fibres overlap with mechanoreceptive fibres in the DRG to integrate information onto the same 2nd neuron

  • Interneuron allows to the relay, processing and modulation of information

• The dorsal horn then projects this information

• Demonstrates how C-fibre input can be modulated

Pain Gate Theory - Wll and Melzak (1960)

• C-fibre projections excite 2nd order projection neurons (which transmit pain) and inhibit spinal inhibitory interneurons (disinhibition).

• Activation of Aβ fibres (mechanoreceptive, low-threshold, myelinated) excites inhibitory interneurons, reducing 2nd-order neuron signal output.

• This explains why rubbing a wound reduces pain — it activates Aβ fibres, which inhibit the projection of pain

  • dampening down of a pain signal through non-nociceptive mechanoreception

• Demonstrates how C-fibre output can be modulated

Mechanism of Aβ Fibre-Mediated Pain Inhibition

• Aβ fibre activation → stimulates inhibitory interneurons in the spinal cord.

• These reduce output from 2nd order projection neurons, dampening the pain signal.

• Shows how non-nociceptive input can suppress nociceptive transmission — a form of top-down modulation.

Referred Pain

• Poor localisation of pain - the feeling of pain at the distal area, away from the site of injury

  • occurs in areas that lack fine distribution of sensory input

• 2 nociceptive fibres from different regions (e.g. skin, chest, internal organs like intestines) synapse on the same second-order projection neuron in the spinal cord.

• When nociceptors at the site of injury (e.g. internal organ) are activated, their signalling molecules may diffuse due to close proximity of presynaptic endings.

• This can simultaneously activate another synapse (e.g. from the skin) even if the sensory end of that fibre hasn’t been stimulated.

• The brain receives the signal as though both areas are activated, causing pain to be perceived in the wrong location

Examples of Referred Pain

• 1. e.g. intestinal pain sensed through silent nociceptors.

  • Synapses on the same projection neuron as nociceptive input from a distal site (e.g. skin).

• 2. E.g. pain from myocardial infarction often felt away from the heart (as far as the jaw)

Central Pain Pathway

• When a nociceptive signal enters the spinal cord:

  1. Signal modulation occurs as it’s processed (either increased or decreased).

  2. The nociceptive signal crosses to the contralateral side of the spinal cord and then ascends through to the brainstem (medulla and pons) and the brain itself .

  3. The signal travels through the spinothalamic pathway to the thalamus where it will then be transmitted to the rest of the brain

Central Pain Pathway: Thalamus

• It integrates sensory information and modulates signals before sending them to the appropriate areas of the brain.

• Nociceptive information is encoded and processed in the thalamus before being projected to:

  • Somatosensory cortex (important for detecting the sensory properties of pain)

  • Cingulate cortex (important for emotional aspects of pain)

Central Pain Pathway: Somatosensory Information

• Does not cross to the contralateral side at the spinal cord level.

• Ascends and crosses to the opposite side further up the spinal cord/brainstem.

Central Pain Pathways: Spinal Reticular and Spinal Mesencephalic Pathways

• These pathways allow pain information to travel into the CNS via afferent fibres, where it’s processed by the brain and ultimately perceived as pain.

Descending Pain Pathway

• Controls pain pathways from the brian to the spinal cord

• Originates from many different areas of the brain including: Insular cortex (IC), Hypothalamus (H). Amygdala (A)

• These regions project down to the periaqueductal grey (PAG) in the midbrain.

• PAG neurons project down to the rostral ventromedial medulla (RVM).

• RVM neurons then project to the second-order neurons in the spinal cord.

• This pathway can modulate how second-order neurons in the spinal cord respond to sensory input from Aδ and C-fibres.

  • Process is similar to "pain gate" → brain influences the spinal cord's processing of pain signals before they are sent to the brain.

Evidence for Top-Down Modulation

• Electrical stimulation of the PeriAqueductal Gray (a brain region that projects to the spinal cord) leads to selective analgesia, reducing pain without affecting other sensations.

  • This provides targeted modulation of pain perception.

• Injection of opioids at various sites leads to selective analgesia, effectively reducing and modulating pain signals.

Role of Periaqueducal Gray (PAG) in Pain Modulation

• This structure projects down to and stimulates various regions, including the locus coeruleus (LC) and raphe nuclei, which release norepinephrine (NE) and serotonin (5HT), respectively.

• These projections activate spinal interneurons in the dorsal horn, which contain enkephalin (an endogenous opiate).

Mechanism of Interneuron Inhibition in Pain Modulation

• Enkephalins (endogenous opiates) decrease the excitability of projection neurons that transmit nociceptive information to the brain - elicit inhibitory controls of the synapse, decreasing the signal that passes as the nociceptive output to the brain

• NE and 5HT activate spinal interneurons, which release enkephalin, inhibiting the synapse between nociceptive sensory neurons and second-order projection neurons = decreased excitability through ↓ Ca2+

• This reduces the influx of Ca²⁺, dampening down the pain perception and preventing it from being transmitted upwards.