pain processing

what is the definition of pain?

an unpleasant sensnory and emotional experience associated with acute or potential tissue damage, or described in terms of such damage

this involves the higher centres in the CNS

what is nociception?

the neural process of encoding noxious stimuli

what is acute (normal) pain?

a warning device, essential to survival that allows avoidance, rest, healing, learning and memory 

• this is normally only elicited by noxious stimuli 

• normally stops on removal of the stimuli/once tissue is healed 

• mechnoreceptive, thermoreceptive, exogenous and endogenous chemicals

what is the structure of a nociceptor?

• free nerve enddings found in most tissues (not CNS)

• nerve endings activated by high threshold stimuli (mechanical, thermal chemical)

• receptive ending contains transducer proteins to detect noxious stimuli

• axon conducts from periphery to spinal cord

• axon canbe thinly myelinated (a delta) or unmyelinted (c fibre)

• cell body in dorsal root ganglion for body and trigeminal ganglia for face

• central terminal projects into the dorsal horn of the spinal cord (lamina I and II) and releases neurotransmitters

what are the two classes of nociceptive fiberes?

a delta and c fibres

what are a delta fibres?

• small diameter and myelinated 

• nociceptive specific 

• thermal and mechanical nociceptors 

• codunction velocity of 5-30 m.s-¹ (fast)

• fast, sharp and well localised pain

• first pain 

• quick onset, short duration

• primary glutamate

what are c fibres?

• unmyelinated

• polymodal detection (mechanical, thermal, chemical etc)

• conduction velocity of <1m.s^-1 (slow)

• dull, aching and burning pain 

• second pain

• glutamate and neuropeptides

• 20% are silent nociceptors (become awakened during inflammation and dont respond to noxious mechanical/thermal stimuli)

what is transudction?

the process by which physical or chemical stimulus is converted into an electrical signal (receptor potential) in a sensory neuron

what are the mechanisms of mechanotransduction?

1. high threshold mechanoreceptors

2. mechanosensitive cation channels 

examples include: merkel cells, meissners corpuscles, ruffini endinfs, pacinian corpuscles, muscle spindles, golgi tendon organs

mechanical deformation of the skin or tissue physically stretches the membrane of the receptor allowing sodium and calcium to eneter

what are high threshold mechanoreceptors?

sensory nerve endings that only respond to intense mechanical stimuli like pinching, cutting and strong pressure 

• found in skin, muscles, joints and viscera 

• express mechanosensitive ion channels 

what are mechanosensitive ion channels?

ion channels that open when the cell membrane is physically deformed by mechanical force 

• allow sodium and calcium to enter

• examples include piezo1 (stretch) and 2 (touch), TRPA1 and TRPV4 (noxious mechcanical stimuli)

• transuce the mechanical force into electrical signal

what are the mechanisms of thermotransduction?

• transient receptor potential channel receptors

• heat gated carion channels

• cold gated channels 

• found in free nerve endings of alpha delta (cold) and c fibres (warm) 

what are transient receptor potential channel receptors?

large group of ion channels (non-selective cation channels) that act as molceular sensors

many major subfamilies 

what is TRPV1?

detects temperatures above 43 degrees

e.g capsaicin and hydrogen (acid)

what is TRPV2?

responds to heat above 52 degrees

what is TRPM8?

responds to cold below 25 degrees

e.g menthol

what is TRPA1?

responds to cold below 17 degrees (and irritants)

what are TRPV3/4?

responds to temperatures between 25-39 degrees

what are the mechanisms of chemotransduction?

• activated by a range of chemicals: external irritants (exogenous) or substances released during tissue damage and inflammation like histamines and bradykinin (endogenous)

• free nerve endings of c fibres 

what are some examples of nociceptors that respond to chemicals?

1. ASIC (acid-sensing ion channels) = respond to protons (H+)

2. P2X receptors = respond to ATP

3. TRPV1 = responds to heat and acid 

4. bradykinin receptors (B1/B20 = activate signalling cascades (PKC/PKA) that sensitise the neuron

what are polymodal nociceptors?

a type of nociceptor that can detect multiple kinds of noxious stimuli

• usually c fibres 

• very little or no adaptation 

• respond to mechanical, chemical and thermal stimuli

• e.g TRPV1

what are the principle neurotransmitters of primary afferents in the spinal cord?

1. glutamate = released from AMPA and NMDA receptor which results in fast excitatory transmission

2. substance P = acts on NK1 receptors on dorsal horn neurons, co released with glutamate from C fibres,  causing slow depolarisation 

3. CGRP (calcitonin gene-related peptide) = co-released with substance P from c fibres, slow excitation

what are the principle neurotransmitters of primary efferents in the periphery?

1. substance P = vasoactive, binds to NK1 receptors on enodthelial cells which increases vascular permeability, edema and histamine releases causing neurogenic inflammation

2. CGRP = vasodialtor which increases blood flow causing redness and warmth

what is the basic overview of nociceptive afferent neurons?

• small neurons

• c fibres

• SP and CGRP

• neurogenic inflammation

• high treshold activation

what is the basic overview of low threshold afferent neurons?

• large neurons

• a delta 

• no SP, little CGRP

• no neurogenic inflammation

• low threshold activation

what are the 3 asecdning nociceptive pathways?

1. spinothalamic

2. spinoreticular 

3. spinomescenphalic

what is the spinothalamic tract?

carries somatic (sharp, well localised)pain, thermal sensations ans crude touch

• first order neurons in DRG 

• second order in dorsal horn: lamina I = pain and temp, lamina IV-VI = crude touch

• decussation at anterior white commissure, contralaterally ascend

• third order in VPL which project to somatosensory cortex, cinguate gyrus and insula (affective response)

what is the spinoreticular tract?

part of the anterolateral system however is involved with dull aching pain (c fibres), emotional aspects of pain 

• first order neurons in DRG 

• second order in dorsal horn (lamina VII and VIII)

• decussate and ascend bilaterally 

• third order neurons in medullary and pontine reticular formation 

• fourth order neurons in thalamic intralaminar nuclei 

• project to somatosensory cortex, thalamus, cinngulate gyrus, insula 

• promotes behvaioural arousal (wake up and pay attention when hurt)

what is the spinomesencephalic tract?

part of anterolateral system and modulates pain

• first order neurons in DRG 

• second order in dorsal horn (lamina I and V)

• decussate at anterior white commissure and ascend contralaterally

• project to PAG and NRM, superior colliculus and tectum

• this can inhibit pain

what is the difference between the lateral and anterior spinothalamic tracts?

• lateral = pain and temp (a delta and c)

• anterior = crude touch and pressure (a delta)

how do fibres differ when considering ouch, ow and ahh?

ouch= a beta (low threshold pressure)

ow = a delta (~0.1s, cutaneous)

ahh = polymodal c fibres 

what are the different inputs of nociceptive fibres to the spinal dorsal horn?

• lamina I (marginal) = sharp localised pain, mainly a delta

• lamina II (substantia gelatinosa) = slow burning, mainly c fibres

• lamina III-IV = mainly a delta and some convergence from c fibres, usually low threshold mechanoreceptors 

• lamina V = noxious and non-noxious, a delta, beta and c fibres = wide dynamic range neurons

• lamina VI-IX = proprioception

what is the gate control theory of pain?

suggests that pain is not a direct result of nociceptor activation, rather it is modulated by intercations between a beta, a delta and c fibres and interneurons

there is a gate in the spinal cord that can increase or decrease pain signals travelling to the brain

what are the processes in the gate control theory?

1. nociceptive input enters lamina I and II releasing excitatory neurotrasnmitters glutamate and substance P

2. this opens the gate, increases WDRN firing and sends pain signals to the brain

3. non-nociceptive (a delta) input enters lamina III-IV and excite inhibitory interneurons in lamina II (GABA/glycine), this inhibits WDRNs in lamina V which closes the gate and pain signal is reduced

what nerves make up the opthalmic branch of the trigeminal nerve?

• supraorbital

• supratrochlear

• frontal

• nasocillary

what nerves make up the maxillary branch of the trigeminal nerve?

• zygomatic

• infraorbital

what nerves make up the opthalmic branch of the trigeminal nerve?

• mental

• lingual

• buccal

• inferior alveolar

• auricolotemporal

what are the 3 nuclei of the trigeminal sensory nuclear complex and which part is resposible for pain?

1. nucleus oralis

2. nucleus interpolaris 

3. nucleus caudalis = pain and temperature processig from the face, oral cavity, cornea and meninges, equivalent of lamina I-II of spinal dorsal horn

what is subnucleus marginalis?

lamina I

what is subnucleus gelatinosa?

lamina II

what is subnucleui magnocellularis?

lamina IV and V

whar are the sensory (discriminative) components of pain?

• perecption/detection dependent on intensity, location and duration 

• components of ST 

• somatosensory cortex 

what are the affective (cognitive) components of pain?

• emotional response

• coping (autonomic, motor, endocrine)

• learning and memory

• components of STT, SRT and SMT

• insular, cingulate, hypothalamus and amygdala