Neurophysiology of Nociception

• "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage" (International Association of Pain)

  Pain you experience can affect your emotions, emotions you're experiencing can affect the pain you experience

  There doesn't have to be visible damage for pain to have been triggered
• Nociception is the release of the substances that can then be detected as pain. Therefore pain is when we interpret it in the brain itself, whereas nociception is the transmission of that signal up to the brain - up until the point it's detected as pain, it's nociception.
• Nociception refers to mechanisms that provide notice of potential noxious substances/stimuli or injury.
• Ganglion = an encapsulated neural structure containing a collection of cell bodies of neurones - important for transmitting the signal.
• Afferent = a sensory nerve passing impulses from receptors to the central nervous system (CNS)
• Efferent = a motor nerve conveying information from the CNS to muscles/glands
• Pain in the orofacial region is transmitted mainly by the CN 5 (trigeminal nerve). Exception angle of the jaw which is supplied by the upper cervical nerves. Branches are the ophthalmic (V1), the maxillary (V2), and the mandibular (V3) divisions. A further anterior and posterior division exists for the mandibular. There are sympathetic and parasympathetic fibres associated with trigeminal nerve.
• The thalamus processes and relays sensory information to the varying parts of the brain. It plays a major role in motor systems.

  
• The cerebral cortex is responsible for memory, language skills and consciousness. It governs voluntary motor control.

  
• Algogenic substances = substances associated with a pain signal - brain detects these substances and interprets them as pain
• Algogenic substances are detected by nociceptors

  
• Nociceptors = receptors on a neurone (nerve fibre), which detect the actual/potential noxious stimuli. They respond to chemical, thermal or mechanical stimuli. Some (up to 30% in most tissues) are silent and are waiting to be recruited.
• There are 2 main types of nociceptive axons (fibres):

  • A-delta (1st/fast)
  • Fast, myelinated
  • Respond to noxious high intensity mechanical stimuli
  • Fluid movement within the tubules causes the nerve within the tubules to stretch - as a result, it's detected as short, sharp pain
  • If this is the case in dentistry - this type of pain means it's either reversible pulpitis or dentine hypersensitivity
  • C-polymodal (2nd/slow)
  • Unmyelinated, slower
  • Respond to mechanical, thermal and chemical stimuli
• There is very little crossover within the trigeminal ganglion. Therefore, the topography of the impulses (the relationship between the site that generated the impulse and the impulse) largely stays the same going into the brainstem.

  
• Throbbing pain or triggered by cold - continues beyond 1 min - C fibre pain.

  • Responds to a range of stimuli
  • Irreversible pulpitis - A delta fibres are in the dentine (further out) and detect early insults - C fibres are in the centre of the pulp, so if they become inflamed then we know that a large majority of the tooth has become inflamed
• Brainstem - trigeminal nucleus caudalis (TNC):

  • The primary afferents in the sensory root of the trigeminal nerve go into the sensory nuclei of the TNC. Composed of:
  • Mesencephalic nucleus - responsible for proprioception from the periodontal ligaments and muscle fibres in the jaw close reflex
  • Principal nucleus - responsible for proprioception for all orofacial behaviour except for the jaw close reflex (e.g. kissing, smiling, talking)
  • Spinal (spinal tract or dorsal medullary horn) nucleus - receives the majority of nociception from the primary afferents of the trigeminal nerve
• The importance of second order neurones:

  • Second order neurones take the information from the synapses, made with primary afferents in the spinal nuclei, up the brainstem, and feed back to the spinal nuclei as they ascend which can be used to help modulate pain
  • Second order neurones travel to the thalamus where they synapse with third order neurones. These go to the higher centres in the brain (cortex) which allow the individual to experience and interpret pain (it was nociception up to this point)
• A descending (motor) response is sent out by the brain once it has interpreted the  signals presented to it from the periphery.

  At the level of the spinal nucleus, the neurone links and synapses with another neurone that's present. The primary/afferent takes it there, then synapses with a second order neurone, which will take the signal higher - has the potential here for signals to get mixed up - can also be useful though; the body can use it to dampen down the signal it crosses over for any further signals that are coming higher (important for managing pain).
• Modulation of nociception:

  • Other than:
  • Altering stimulus (e.g. tapping on the tooth more gently)
  • Pharmacological alteration/interruption nociception (analgesia, anaesthesia)
  • Two main mechanisms of modulation (that can happen in the body itself):
  • Descending impulses
  • Sensitisation

  
• Descending impulses from the brain:

  • Affect transmission of impulses from primary afferents
  • 1 route = affects areas in the Periaqueductal grey matter (mid brain) where there are opioid receptors => sends signal to Medulla (Nucleus Raphae Magnus) => then sends it to Trigeminal nucleus, where there's a release of serotonin
  • Endogenous chemical messenger (opioids)

  This can affect things centrally and peripherally
• Gate control:

  • Aβ (vv fast proprioception - faster than A delta)
  • Brings further stimulus centrally
  • Generates descending impulse
  • Causes closure at gate area (Trigeminal nucleus Caudalis 2nd order point)

  As the Aβ signal comes higher, it then resends the signal, which makes it harder for A delta or C fibre signals to be interpreted by the second order neurones, therefore closing the gate and helping modulate pain from going higher.

  Examples of this in practice = tens machines

  
• Sensitisation:

  • Progressive increase in response following concurrent repeated experience of a stimulus:
  • Hyperalgesia (increase in painful signal)
  • Allodynia (a signal which previously would not have been interpreted as painful is now interpreted as such)
  • Occurs as a peripheral and central sensitisation
  • Protetive but... role in chronic pain
• Peripheral sensitisation:

  • When inflamed peripheral nociceptors can have increased responsiveness or respond to lower thresholds
  • Stimulus of nociceptors may be more persistent and intense (hyperalgesia)

  Caused by constant chronic tissue damage releasing continual allogenic substances.

  This constant barrage:

  • Recruits sleeping/silent nociceptors to increase impulses to the brain
  • Makes nociceptors prone to spontaneous activity (happens when they're inflamed/damaged)
  • Lowers nociceptive thresholds in nociceptors
• Constant chronic tissue damage releasing continual allogenic substances recruits sleeping/silent nociceptors to increase impulses to the brain. This is the reason for hyperalgesia; more nociceptors/more axons are firing towards the trigeminal nucleus caudalis and sending to more secondary neurones.
• Peripheral sensitisation can also result in allodynia, where we can have lower thresholds to signals. So something that would previously have to have generated a certain action potential for the signal to be transmitted, now has that threshold lowered, so anything above a lower amount will trigger this same response.
• Central sensitisation:

  • If second order neurones receive prolonged stimulus of nociceptive input it may become sensitised
  • May increase strength of pain sensation (hyperalgesia)
  • May lead to painful sensation from otherwise non-painful trigger (allodynia)
• Central sensitisation (neuroplasticity) occurs as a result of a number of factors:

  • Nerve trauma
  • Hormonal, genetic and environmental factors
  • Local factors (peripheral sensitisation)
  • If peripheral happens and continues beyond the healing process, there's a good chance that can lead to central sensitisation - why it's important to manage pain effectively at an early stage to prevent it becoming something more persistent
  • Psychological factors
  • Glial cells
• Convergence:

  • The brain struggles to tell which area an impulse originally came from
  • This results in referred pain where the brain interprets a pain as coming from one area, but the pain is from elsewhere
  • The analogy of travelling can explain convergence. There are many paths that get you to the same destination and some of these other paths may even cross the main path to your chosen destination. On your way you could, therefore, get confused and change direction/path but end up at the same destination
• Divergence is radiation of pain. It occurs because of the potential for primary afferents to synapse several second order neurones, therefore sending impulses to the brain that appear to be from a larger area than the original site of noxious stimulation. Using travelling again - with 'divergence', multiple people start out on the same path to a destination, but each choose different paths at crossroads in the original path they set out on, therefore covering a large area on the way to the destination.
• Modulation of nociception:

  • Sensitisation
  • Peripheral - caused by constant persistent tissue damage releasing continual algogenic substances
  • Central - caused by number of factors: local factors (peripheral sensitisation), nerve trauma, hormonal, genetic and environmental factors, Glial cells, psychological factors
• Persistent idiopathic dentoalveolar pain (PIDP):

  • Previously used terms: atypical odontalgia, primary dental alveolar pain (PDAP), phantom tooth pain
  • Pain from an area where a tooth/nerve has been removed that is causing persistent, or chronic pain
  • Description: unilateral, or rarely multiple sites of intraoral dentoalveolar pain with varying presentations but recurring daily for more than 2 hours per day, over more than 3 months without close temporal preceding event
• Persistent idiopathic dentoalveolar pain (PIDP) diagnostic criteria:

  • Unilateral, or rarely multiple sites of intraoral dentoalveolar pain fulfilling criterion B and C
  • Recurring daily for > 2 hours per day for > 3 months
  • Pain has both of the following characteristics:
  • Localised to dentoalveolar site or sites (tooth or alveolar bone)
  • Deep, dull, pressure-like quality
  • Clinical and radiographic examinations are normal and no local cause may explain the pain
  • Not better accounted for by another ICOP or ICHD-3 diagnosis
• Warning signs of a persistent pain:

  • Pt may have difficulty localising pain (may affect multiple teeth)
  • No obvious source of local pathology
  • Pain described as burning or electric shock (no longer sharp, or throbbing)
  • Numbness or tingling present
  • Failure of LA to provide pain reduction
  • Pain extending beyond the usual timeframe of healing
  • Repeated treatments which have failed to resolve pain
  • Pain has unusual triggers and abnormal response to usual odontogenic pain triggers i.e. percussion or temperature changes
  • History of past trauma to the area
  • Pain does not disturb patient's sleep
• Biopsychosocial model of pain - use in management of persistent pain:

  • Multidisciplinary management
  • Persistent orofacial pain is estimated to have a similar impact upon quality of life as depression and rheumatoid arthritis
  • Psychosocial interventions
  • Aim to improve the patient's management and reduce impact upon quality of life
  • Cognitive techniques
  • Cognitive behavioural techniques (CBT) ~50% reduction in TMD patients pain after 1 year

  
• Nociception and pain are different. Nociception is the signal, pain is when it's interpreted in the cortex.
• Pain is biopsychosocial. Pain is an emotional response, and that can affect the signal of how it's interpreted and can also affect the patient's mood. Interpretation of nociception in the context of:

  • Genotype, phenotype (psychology, sociology) of patient
  • Situation, environment, culture, etc.
• Pain can be modulated (for both good and bad). Pain can be present in absence of noxious stimuli and is real.