ACFiber

A Comparison of the A-d and C-Fiber Nociceptors

General Properties	A-d	C-Fiber
Mylenation	Mylenated	Unmylenated
Diameter Ref. Fields, p.16	2-5 m m	0.3-3.0 m m
Fiber Classifications Ref. Wall, p.14	A-Fiber Mechano-Heat nociceptors (AMH) --- AMH I: High Heat Receptors --- AMH II: Low Heat Receptors	C-PolyModal Nociceptor (C-PMN)
General Characteristics of Pain associated with each Fiber Type	"First Pain": Early, Brief, Sharp, and Pricking Ref. Fields, p.25	"Second Pain": Slow, Dull, and Burning Ref. Fields, p.25
Conduction Properties	A-d	C-Fiber
Conduction Velocity Ref. Melzack, p.86	6-30 m/sec.	1-2.5 m/sec
Action Potential Properties Ref. Wall, p.59	Amplitude = 73 mV Overshoot = 20 mV Rate of Rise 458 V/S Duration = 1.0 ms There is no inflection on falling Phase Blocked by TTX Amplitude, fter-potential = -5.9 mV Duration, After-potential = 3.8 ms	82 mV 32 mV 227 V/S 5.0 ms There is an inflection on falling Phase Partly blocked by TTX Amplitude, after-potential = -8.2 mV Duration, After-potential =12.9 ms
Sodium Currents	TTX Sensitive only	TTX Sensitive TTX Insensitive
Potassium Currents	Delayed Rectifier N/A	Delayed Rectifier Transient A-Current (some cells)
Calcium Currents	N/A	Low Threshold (T)
	High Threshold (L)	High Threshold (L)
	High Threshold (N)	High Threshold (N)
Calcium Channel Types	L-Channels N-Channels	L-Channels N-Channels T-Channels
Neuro-secretory Chemicals	A-d	C-Fiber
Chemicals Secreted by Fiber	Excitatory amino acids (glutamate, aspartate, or ATP) believed to be the neurotransmitter Ref. Fields, p.51 A-d fibers do not contain peptides. Ref. Melzack, p.101	Substance P (however, there are C-nociceptors without Substance P) Ref. Fields, p.51 Neurokinins A&B Cholycstokinin CGRP Vasointestinal peptide Ref. Melzack, p.104. In functions mediated via peripheral terminals of afferent C-Fibers, only neuropeptides appear to be involved Ref. Juranek, p.663
Chemicals Secreted *Ref. Yeomans, D.C., Youngwerth, J. and Proudfit, H.K.*	Excitatory amino acids DNQX is an AMPA/Kainate antagonist which increases latencies for high heat rates and low heat rates. Therefore excitatory amino acids released from A-d and C-Fiber nociceptors act on non-NMDA receptors to produce nociception.
Location and Release of Glutamate and Substance P Ref. Juranek, p.663	N/A	Glutamate and Substance P co-exist in primary afferent C-Fibers. Co-released by appropriate stimuli from the central terminals. Substance P potentiates glutamate-mediated electrophysiological responses of spinal dorsal horn neurons
Response Properties	A-d	C-Fiber
General Sensitivities	Relatively insensitive to Heat and Chemicals	Mechanical, Thermal, and Chemical
Responds to…	Light Pressure Heavy Pressure Heat (45+ deg. Cent.) Chemicals Cooling	Light Pressure Heavy Pressure Heat (45+ deg. Cent.) Chemicals Warmth
Primate Heat Threshold Ref. Wall, p.14	The majority of AMH fibers have thresholds of 53° C or greater	In primates, typically greater than 38° C but less than 50° C
Response properties to probes Ref. Garrell, pp.1187-88	Response range associated with sharpness thresholds (5-6 imp/sec) is completely separate from response range associates with pain (8-10 imp/sec.) because A-Fibers show a greater response differentiation across probes than do C-Fibers. A-Fiber MSAs show response saturation close to pain threshold. A-Fiber MIAs continue to show increasing stimulus response functions above pain threshold. Activity in the A-Fiber nociceptors determine threshold levels of sharpness and pain perception	Response rate associated with two perceptual thresholds are overlapping.
Effect if mylenated fibers are blocked selectively Ref. Fields, p.59	"First Pain" (pricking sensation) disappears	Perception of noxious skin stimuli due to unmylenated fibers seem more painful, i.e., the "Second Pain" is enhanced
Rates of heating which selectively activate fibers Ref. Yeomans and Proudfit, p.148-149	High rate of heating (6.5° C/Sec.) selectively activates Ad Fibers.	Low rate of heating (0.9° C/Sec.) selectively activates C-Fibers
Reflexly evoked increase in release of enkephalin, norepenephrine, and serotonin	N/A	Occurs consequent to C-Fiber activation Ref. Wall, p.172
Comparison of the responsiveness of MIAs and MSAs	There is no difference in heat or chemical responsiveness between MIAs and MSAs Ref. Garell, p.1184	More MSAs than MIAs were heat sensitive. Heat thresholds were comparable for both types. No correlation found between mechanical and thermal thresholds for individual units Ref. Garrell, p.1185
Receptive Fields	A-d	C-Fiber
Cutaneous Receptive Fields	Clusters of Spots, approx. 1mm diameter Ref. Fields, p.20	Singular Areas Ref. Fields, p.22
Receptive Field Properties Ref. Garrell, p.1186-1187	Very small spots separated by insensitive regions <200micrometer-diameter spots separated by 1-5mm.	Appears as a single continuous receptive field over 1mm in diameter because C-Fiber sensitive spots are larger and closer together. Spots are only distinct when <=0.3mm diameter probes were used
Response Properties Ref. Garrell 1186	Responds in proportion to force applied, however, A-d fibers exhibit a greater differential response related to probe size than C-Fibers	Responds in proportion to force applied
Response to Probe Size Ref. Garrell 1187	Differential response across all probe sizes	Differential response only with larger probes. Therefore exhibits differential response to large stimulus intensity metric: Compression force, Shear force, Force gradient, Strain energy density, etc.
Pain Characteristics Ref. Garrell, p.1118	Responsible for mechanically-evoked pain. Gives "sharp" sensation	Gives "burning" sensation. C-Fibers respond to mechanical stimuli, but mechanical stimuli do not cause burning pain which is the type of pain C-Fibers are responsible for. This is because of the differential response property of the nociceptor discussed supra.
Effect of MU opioid agonists on receptive field		Diminish size of high threshold C-Fiber receptive field Ref. Wall, p.170
General Characteristics of Axon Terminals Ref. Fields, p. 27	Terminals wrapped in Schwann Cell Sheath --- Peripheral Terminal itself is Mechanosensitive No Separate receptor cell	No Data Available. Ref. Fields, p. 27
Receptors	A-d	C-Fiber
Organization of Dorsal Horn: INPUTS Ref. Wall, p.101	· Cold Cutaneous Thermoreceptor · Visceral Mechanoreceptor for Distension · High Threshold Cutaneous Mechanoreceptor · High Threshold Cutaneous Thermoreceptors · High Threshold Cutaneous Polymodal (incl. chemo) · High Threshold Muscle Mechanoreceptor · High Threshold Joint Mechanoreceptor · High Threshold Visceral Mechanical	· Warm Cutaneous Thermoreceptor · High Threshold Cutaneous Thermoreceptor · High Threshold Cutaneous Polymodal (incl. chemo) · High Threshold Cutaneous Silent · High Threshold Muscle Mechanoreceptor · High Threshold Muscle Chemoreceptors · High Threshold Joint Mechanoreceptor · High Threshold Visceral Mechanical · High Threshold Visceral Polymodal
Receptor type Ref. Melzack, p.86	Free	Free
Receptors	A-d	C-Fiber
Entry into the Spinal Cord Ref. Fields, p.48	Some enter via the ventral root	Some enter via the ventral root
Input is sent to… Ref Fields, p.59	A-d fibers send input to Lamina I neurons (projection neurons)	C-nociceptors send input to Lamina I neurons (projection neurons)
Site of Terminals	Lamina I and V (NOT Lamina II) Ref. Fields, p.45	Lamina II Ref. Wall, p.109
Inhibition of Nociceptive Responses by Afferent Input Ref. Fields, p.59-61	Mylenated nociceptors send input to the spinal cord early. This input activates an inhibitory interneuron which produces a lingering inhibition that suppresses the response of the projection cell to later-arriving input from unmylenated nociceptors
Effects of Chemicals	A-d	C-Fiber
Activation by Capsaicin Ref. Szolcsanyi, p.323	A-d mechanoheat-sensitive nociceptors activated by Capsaicin 5 micrograms of Capsaicin excited few "slowly adapting" A-Mechanoreceptors after a long latency, but not cutaneous A-d mechanoreceptors or other cutaneous receptors.	C-polymodal nociceptors activated by Capsaicin. Proportion of C-Polymodal nociceptors was decreased. Proportion of C-mechanoreceptors was increased after systemic treatment.
Effects of Mustard oil: Ref. Melzack, p.103	None	Selectively stimulates fibers for approximately 5 minutes
Ref. Szolcsanyi, p.323		Thresholds for pain sensation evoked by irritant chemicals bradykinin, noxious heat, but not mechanical stimuli were markedly elevated on skin desensitized by topical application of Capsaicin
Activation of NK-1 receptors		Release of Substance P and CGRP activate NK-1 receptors Ref. Juranek, p.661
Inhibition of Glutamate release Ref. Juranek, p.663		NK-1 receptor antagonist inhibits glutamate release
MK-801 effect on Glutamate Ref. Juranek, p.661		MK-801 is an NMDA antagonist, and has no effect on evoked glutamate release
NMDA Receptors Ref. Juranek, p.661		Activation of central functions mediated by NMDA receptors
NK-1 antagonist Ref. Juranek, p.661		CP-99994 is an NK-1 antagonist and has been found to reduce responses to both Capsaicin and Substance P.
Ref. Juranek, p.661		Capsaicin-evoked glutamate release was markedly smaller than that from dorsal horns
Ref. Juranek, p.661		Normalized responses to capsaicin and substance p were similar
Ref. Juranek, p.661		The observed effect of exogenous Substance P and inhibitory action of NK-antagonist indicates facilitation of Capsaicin-induced glutamate release by co-released Substance P.
Sensitization And Summation	A-d	C-Fiber
Nociceptor Evoked Central Hyperexcitability Ref. Wall, p.213	Ad discharge evokes weak hyperexcitability	C-Fiber input evokes a plastic change in responsiveness of spinal cord dorsal horn neurons Onset of many peripheral neuropathies is accompanied or preceded by C-nociceptor barrages Volleys in musculoskeletal C-Fibers evoke pronounced central hyperexcitability Hyperexcitability involves activity at glutaminergic synapses of N-methyl-D-aspartate (NMDA) type for its initiation and its maintenance
"Wind Up" Effect Ref. Wall, p.170	No Wind Up-like phenomenon	Wind Up phenomenon: Augmented response to further C-Fiber input Mediated by NMDA Subtype glutamate receptor
Summation Ref. Fields, p.59	Summation persists or is enhanced when mylenated axons are blocked.	Summation depends on activity in unmylenated nociceptors
Pathological States	A-d	C-Fiber
Types of Fibers which Sensitize due to tissue injury: Ref. Wall, p.209	Cutaneous Ad fibers and Deep tissue Ad fibers	Deep tissue C-Fibers only
Neurogenic Inflammation Ref. Wall, p.31		Peripheral terminals play an important role in "neurogenic inflammation" mediated by released Substance P and CGRP.
Allodynia, Cause of	A-d fiber sensitization causes Allodynia Ref. Melzack, p.99-100
Effect of Partial Demylenation	Hyperexcitability and Conduction Block Ref. Wall, p.82	Not Applicable: C-Fibers are Unmylenated
Close arterial injection of Adrenalin or Noradrenalin and by electrical stimulation of postganglionic sympathetic efferents in injured afferent fibers	Ongoing discharge is evoked or enhanced Mediated by a -adrenoreceptors Ref. Wall, p.85	Ongoing discharge is evoked or enhanced Mediated by a -adrenoreceptors Ref. Wall, p.85
Neuroma End Bulbs & Sprouts Ref. Wall, p.82	Produce ectopic impulses	Produce ectopic impulses
Relative Axon Conduction Velocity in Rat Neuroma Ref. Wall, p.83	Represented approx. according to their numbers in the nerve 90% of spontaneously active neuroma fibers discharge rhythmically	Underrepresented at short postoperative times Over represented at long postoperative times Nearly all spontaneous neuroma fibers discharge rhythmically
Effect of temperature on ectopic pacemaker firing in neuroma Ref. Wall, p.85	Response to Heating: Neuroma fibers rate of spontaneous discharge increases with warming. Also, previously silent fibers are recruited Response to Cooling: Cooling suppresses firing	Firing suppressed by warming and excited by cooling

References:

Fields, Howard L. Pain. McGraw-Hill, New York. 1987.

Garell, P. Charles, McGillis, Sandra, and Joel D. Greenspan. "Mechanical Response Properties of Nociceptors Innervating Feline Hairy Skin." Journal of Neurophysiology, 75(3), March 1996.

Juranek I, Lembeck F. "Afferent C-fibers release substance P and glutamate." Canadian Journal of Physiology. 75(661) pp. 661-664. (1997)

Melzack, Ronald and Patrick Wall. The Challenge of Pain. Penguin Books, London. 1988.

Szolcsanyi, Janos. "Capsaicin and Nociception." Acta Physiologica Hungarica. 69(3-4) pp.323-332 (1987).

Wall, Patrick and Ronald Melzack (editors). Textbook of Pain, Third Edition. Churchill Livingstone. Longman Group LTD. 1994.

Yeomans, DC and Proudfit, HK. "Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence." Pain. 68 (1996) 141-150.

Yeomans, D.C.; Youngwerth, J.; Proudfit, H.K. Dept. of Pharmacology, Univ. of Illinois at Chicago. "Selectivity of NMDA and non-NMDA Excitatory Amino Acid Antagonists for Nociception Evoked by Activation of C or Ad Nocireceptors in Rats." Society for Neuroscience Abstracts, Vol.20, Abstract No.568.6, 1994.

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