activation of sensory neurons in arthritic pain

Activation of Sensory Neurons in Arthritic Pain

Amitesh Narayan

Pain?

“An unpleasant sensory & emotional experience

associated with actual or potential tissue damage, or

described in terms of such damage” – The International Association for the Study of Pain

Subjective sensation

Pain Sources

Fast vs. Slow Pain – Fast – localized; carried through A-delta axons in skin

Slow – aching, throbbing, burning; carried by C fibers

Nociceptive neuron transmits pain to spinal cord via unmyelinated C fibers & myelinated A-delta fibers.

• smaller C fibers carry impulses @ rate of 0.5 to 2.0 m/sec.

• larger A-delta fibers carry impulses @ rate of 5 to 30 m/sec.

Acute vs. Chronic

Pain Mnemonics

P-Q-R-S-T formatProvocation – How the injury occurred & what activities the painQuality - characteristics of pain – Aching (impingement), Burning (n. irritation), Sharp (acute injury), Radiating Referral/Radiation –

Referred – site distant to damaged tissue that does not follow the course of a peripheral n.Radiating – follows peripheral n.; diffuse

Severity –Pain scaleTiming – When does it occur?

Pattern: onset & duration

Area: location

Intensity: level

Nature: description

Pain Transmitting Nerves

Afferent (Ascending) –from periphery to the brain

First Order neuron

Second Order neuron

Third Order neuron

Efferent (Descending) – transmit impulses from the brain to the periphery

First Order NeuronsStimulated by sensory receptorsEnd in the dorsal horn of the spinal cordTypes

A-alpha – non-pain impulsesA-beta – non-pain impulses

• Large, myelinated• Low threshold mechanoreceptor; respond to light touch & low-

intensity mechanical infoA-delta – pain impulses due to mechanical pressure

• Large diameter, thinly myelinated• Short duration, sharp, fast, bright, localized sensation (prickling,

stinging, burning)C – pain impulses due to chemicals or mechanical

• Small diameter, unmyelinated• Delayed onset, diffuse nagging sensation (aching, throbbing)

Second Order NeuronsReceive impulses from the FON in the dorsal horn

Lamina II, Substantia Gelatinosa (SG) - determines the input sent to T cells from peripheral nerve

• T Cells (transmission cells): transmission cell that connects sensory n. to CNS; neurons that organize stimulus input & transmit stimulus to the brain

Travel along the spinothalamic tract Pass through Reticular Formation

TypesWide range specific

• Receive impulses from A-beta, A-delta, & C

Nociceptive specific• Receive impulses from A-delta & C

Ends in thalamus

Third Order Neurons

Begins in thalamus

Ends in specific brain centers (cerebral cortex)

Perceive location, quality, intensity

Allows to feel pain, integrate past experiences & emotions and determine reaction to stimulus

Descending NeuronsDescending Pain Modulation (Descending Pain Control Mechanism)Transmit impulses from the brain (corticospinal tract in the cortex) to the spinal cord (lamina)

Periaquaductal Gray Area (PGA) – release enkephalinsNucleus Raphe Magnus (NRM) – release serotonin

* release of these neurotransmitters inhibit ascending neurons.

Stimulation of the PGA in the midbrain & NRM in the pons & medulla causes analgesia.

Endogenous opioid peptides - endorphins & enkephalins

NeurotransmittersChemical substances that allow impulses to move from one neuron to another

Found in synapsesSubstance P - transmits pain-producing impulsesAcetylcholine – transmits motor nerve impulsesEnkephalins – reduces pain perception by bonding to pain receptor sitesNorepinephrine – causes vasoconstriction

2 types of chemical neurotransmitters that mediate pain• Endorphins - morphine-like neurohormone; thought to pain threshold by binding to

receptor sites• Serotonin - substance that causes local vasodilation & permeability of capillaries

* Both are generated by noxious stimuli, which activate the inhibition of pain transmission

Can be either excitatory or inhibitory

Sensory ReceptorsMechanoreceptors – touch, light or deep pressure

Meissner’s corpuscles (light touch), Pacinian corpuscles (deep pressure), Merkel’s corpuscles (deep pressure)

Thermoreceptors - heat, coldKrause’s end bulbs ( temp & touch), Ruffini corpuscles (in the skin) – touch, tension, heat; (in joint capsules & ligaments – change of position)

Proprioceptors – change in length or tensionMuscle Spindles, Golgi Tendon Organs

Nociceptors – painful stimuli mechanosensitivechemosensitive

Nerve Endings“A nerve ending is the termination of a nerve fiber in a peripheral structure.” (Prentice, p. 37)

Nerve endings may: Respond to phasic activity - produce an impulse when stimulus is or , but not during sustained stimulus; adapt to a constant stimulus (Meissner’s corpuscles & Pacinian corpuscles)

Respond to tonic receptors produce impulses as long as the stimulus is present. (muscle spindles, free n. endings, Krause’s end bulbs)

Nerve EndingsMerkel’s corpuscles/disks -

Sensitive to touch & vibration

Slow adapting

Superficial location

Most sensitive

Meissner’s corpuscles – Sensitive to light touch & vibrations

Rapid adapting

Superficial location

Pacinian corpuscles -Sensitive to deep pressure & vibrations

Rapid adapting

Deep subcutaneous tissue location

Krause’s end bulbs – Thermoreceptor

Ruffini corpuscles/endingsThermoreceptor

Sensitive to touch & tension

Slow adapting

Free nerve endings -Afferent

Detects pain, touch, temperature, mechanical stimuli

Phenotype classification of primary afferent nerve fibres

Classified a/c to their neuropeptide phenotype: a.Large diameter non-nociceptive neurons and nerve fibres that bind the RT97+ve antibody (Bergman et al 1999) which recognizes phosphorylated epitopes on identified neurofilament proteins (Johnstone et al 1997).

b.Isolectin B4 (IB4) positive neurons, which are non-peptidergic nociceptive neurons (Silverman&Kruger 1990), and

c.Calcitonin gene-related peptide (CGRP)-expressing neurons (McCarthy & Lawson 1990), classed as peptidergic nociceptive neurons, recognized using selective CGRP antibodies.

Spinal Cord and CNS Pathways from Pain Receptors

AAntinociceptive systémntinociceptive systém

Endorphin Response

Articular afferents and inflammation

Trauma to the joint

increased sensitivity to load and movement of the joint within the normal range (allodynia).

increased sensitivity to further noxious mechanical stimulation (Hyperalgesia).

brought about by changes in the

sensitivity of

primary afferent nerve fibres (through spinal processing of joint input and by processing within higher centres).


Following joint inflammation, low threshold group II articular afferents show acute and transient changes in response to joint manipulation which resolve within few hours.

Articular afferents belonging to groups III and IV begin to show ongoing spontaneous activity in the absence of joint movement; BUT

show enhanced responses to joint movements.

Coggeshall et al 1983, Guilbaud et al 1985, Schaible & Schmidt 1988a).


Furthermore, many units which were previously Mechano-insensitive develop receptive fields and may

also show ongoing spontaneous activity. These alterations in the firing characteristics of group III and IV

afferents are the result of a

marked reduction in the mechanical threshold for activation of articular mechanoreceptors and it

contributes, in part, to psychophysical measures of allodynia and hyperalgesia experienced in humans.


In chronic disease, inflammatory response may be protracted due to abnormal pathology in the joint tissues.

In OA, this is largely due to the destruction of cartilage and bone remodelling (osteophytes or bony spurs).

Loss of the normal articulating surfaces and abnormal bone pathology results in chronic inflammation that can last years.

ReferencesBlair D. Grubb. Activation of sensory neurons in the arthritic joint. Osteoarthritic Joint Pain: Novartis Foundation Symposium 260. Volume 260 Edited by Derek J. Chadwick and Jamie Goode. Novartis Foundation 2004. ISBN: 0-470-86763-9.

Coggeshall RE, Hong KAP, Langford LA, Schaible H-G, Schmidt RF 1983 Discharge characteristics of fine medial articular afferents at rest and during passive movements of inflamed knee joints. Brain Res 272:185-188.

Jayson MIV, Dixon ASJ 1970 Intraarticular pressure in rheumatoid arthritis of the knee. I. Pressure changes during passive joint distension. Ann Rheum Dis 261-265.

Johansson H, Sjolander P, Sojka P 1991 Receptors in the knee joint ligaments and their role in the biomechanics of the joint. Crit Revs Biomed Eng 18:341-368.

Schaible H-G, Schmidt RF 1988a Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol 60:2180^2195

ReferencesSchaible H-G, Grubb BD 1993 Afferent and spinal mechanisms of joint pain. Pain 55:5-54.

activation of sensory neurons in arthritic pain

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