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
Pattern: onset & duration Area: location Intensity: level Nature: description
P-Q-R-S-T format
Provocation How the injury occurred & what activities the pain Quality - 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 scale Timing When does it occur?

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 Neurons

Stimulated by sensory receptors End in the dorsal horn of the spinal cord Types A-alpha non-pain impulses A-beta non-pain impulses
Large, myelinated Low threshold mechanoreceptor; respond to light touch & lowintensity mechanical info

A-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 Neurons

Receive 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

Types
Wide 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 Neurons
Descending 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 enkephalins Nucleus 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

Neurotransmitters
Chemical substances that allow impulses to move from one neuron to another Found in synapses
Substance P - transmits pain-producing impulses Acetylcholine transmits motor nerve impulses Enkephalins reduces pain perception by bonding to pain receptor sites Norepinephrine 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 Receptors
Mechanoreceptors touch, light or deep pressure
Meissners corpuscles (light touch), Pacinian corpuscles (deep pressure), Merkels corpuscles (deep pressure)

Thermoreceptors - heat, cold

Krauses end bulbs ( temp & touch), Ruffini corpuscles (in the skin) touch, tension, heat; (in joint capsules & ligaments change of position)

Proprioceptors change in length or tension

Muscle Spindles, Golgi Tendon Organs

Nociceptors painful stimuli

mechanosensitive chemosensitive

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 (Meissners corpuscles & Pacinian corpuscles) Respond to tonic receptors produce impulses as long as the stimulus is present. (muscle spindles, free n. endings, Krauses end bulbs)

Nerve Endings
Merkels corpuscles/disks Sensitive to touch & vibration Slow adapting Superficial location Most sensitive

Krauses end bulbs

Thermoreceptor

Ruffini corpuscles/endings
Thermoreceptor Sensitive to touch & tension Slow adapting

Meissners corpuscles
Sensitive to light touch & vibrations Rapid adapting Superficial location

Free nerve endings Afferent Detects pain, touch, temperature, mechanical stimuli

Pacinian corpuscles Sensitive to deep pressure & vibrations Rapid adapting Deep subcutaneous tissue location

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 nonpeptidergic 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

Antinociceptive systm

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).

Articular afferents and inflammation

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).

Articular afferents and inflammation

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.

Articular afferents and inflammation

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.

References
Blair 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

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