627.

04

Intradermic capsaicin increases autogenic and heterogenic PAD in A articular afferents as part of a
control mechanism that regulates information flow in nociceptive afferents.
Ramrez-Morales A., Hernndez E. and Rudomn P.* Department of Physiology, Biophysics and Neurosciences, CINVESTAV IPN, Mxico.

INTRODUCTION
Previous studies in the anesthetized cat have indicated that, in
contrast with tendon organ afferents (J. Physiol. 1992, 445 p345),
autogenic primary afferent depolarization (PAD) of single afferents in
the posterior articular nerve (PAN) is relatively small (J. Physiol. 1993,
466 p115; Exp. Brain Res. 2007, 176 p119), but can be increased by
capsaicin-induced skin inflammation (Abs. 804.13, 2011).

PAN

SP
5

1.5 1.2

77

77 80

85 100

3
122

5
122

xT
%

2
125

SU
1.5
122

xT
%

1.2
122

1.5

3.8

Control

5
85

3
85

2
85

1.5
100

5
114

1.2
100

3
115

2
110

1.5
121

xT
%

1.2
115

1.2
100

1.5
94

2
85

5
85

3
85

1.2
100

1.5
100

5
86

2
100

5
100

3
100

3
80

2.1

2
83

1.2
100

3
113

2
86

1.5
79

%
120

99

102

100

98

97

99

97

101

98

102

101 100

100

PAD

SP

1.2xT
1.5xT
2xT
3xT

2.5
93

3
93

5
94

4
94

xT
%

13
11

Without
Stimulus

19

PAN 1xT

17
PAN
2.5

5 xT

89

90

91

90

91 %

1.5

10 xT

95

94

82

84

80

99 101 96

93

93

92

92

1.5

2.5

xT

85

90

92

95

180 min.

120

80

110

10 m
V

Circuit diagram to explain the facilitation of autogenic PAD

of Ad
articular afferents following the intradermic injection
of capsaicin

Supraspinal
Structures

+
CAPSAICIN

Laminae I-II

v.

Laminae
III-VI

140

105

PAH

PAH

PAD

Low-Threshold
Cutaneous afferents

100

85

+
+

PAD

120

90

Re

Blo
ck
al

Articular Ad
-afferents

Sp
in

CA
P1

80

mi
n.

mi
n.
20

0m
in.

CA
P1

Sp
in

CA
P6

nje

ol

Blo
ck
Re
CA
v.
Pi
nje
ctio
CA
n
P6
0m
CA
in .
P1
20
mi
CA
n.
P1
80
mi
Sp
n.
ina
lB
loc
k
Re
v.

ntr
Co

ctio
n

90
ol

ctio
CA
n
P6
0m
CA
in .
P1
20
mi
CA
n.
P1
80
mi
Sp
n.
ina
lb
loc
k
Re
v.

v.

CA
Pi

80
80
60
75
mi
n.
20

Low-Threshold
Articular afferents

CA
P1

ntr
ol

n=7

Co

mi
n.

CA
P1

ntr
ol
Co

mi
n.
80

CA
P1

ntr
ol
Co

mi
n.
20

CA
P1

0m
in.

CA
P6

nje

ctio
n

v.
Re

CA
Pi

Blo
ck
al

Blo
ck
al

Sp
in

80

mi
n.

mi
n.
CA
P1

20

CA
P1

0m
in.

n=3

n=4

70

80

40

CA
P6

2 ms

40

45

50 m/s

Changed after CAP

Autogenic
PAD

Autogenic
PAH

No change after CAP

Effect
<10%

Intraspinal threshold changes of single articular afferents produced by PAN stimulation are expressed as
percentage changes relative to control. Threshold changes above 100% indicate PAH and changes below
100% indicate PAD. Graphs show threshold changes during reversible spinal block by cooling (blue bars)
and 10 - 210 minutes after the intradermic injection of capsaicin (red bars). Intensity of PAN nerve
stimulation varied between 1.2 and 10 xT and is indicated by different symbols. Note that in A, B and C
spinal block reduced the autogenic PAH. After capsaicin, autogenic PAN stimulation produced PAD that
was reduced during spinal block. In D and E autogenic stimulation produced PAD that was increased after
capsaicin. F shows the effects of capsaicin (red symbols) on autogenic PAH and PAD.

2 mm
2 mm

A, Autogenic PAN stimulation with pulses 1 - 2xT had no effect on the intraspinal threshold of
a single articular fiber, while stimuli above 2.5xT produced PAD. After capsaicin injection,
autogenic PAD was produced with stimuli 1.5xT. B, The peripheral threshold of the tested
afferent was between 2 - 2.5xT as determined by colliding the antidromic response with PAN
stimulation. Histology shows location of the site excitability testing.

Cutaneous Ad
-afferents

ctio
n

35

24

1 min.

100

CA
Pi

30

Conduction Velocity

19

130

90

nje

Re

ck
blo

al

25

PAN

100

90

20

140

110

95

6
5
4
3
2
1

20

Before capsaicin, autogenic (PAN) and heterogenic (SP, SU and Saph)

conditioning stimulation had no effect on the intraspinal threshold of the
afferent fiber. Two hours after capsaicin injection, PAN as well as SP and SU
conditioning stimulation produced a strong PAD, while the Saph stimulation
had no effect. Articular fiber with peripheral threshold of 4xT; CV, 37.5 m/s.

PAD

PAN 2xT

24

2 min.

50

100

Antidromic
Stimulation

PAN 2.5xT

xT

m
A

60

PAH

PAN
Stimulation

m
A

120 min.

PAN

Saph

ntr

5xT
10xT

Co

Cats anesthetized, paralyzed and artificially ventilated. The left posterior articular nerve (PAN) was
disected free, sectioned and its central end mounted on two pairs of hook electrodes, one for
stimulation and the other for recording the antidromic responses of single fibers. The superficial
peroneal (SP) was left intact and the Sural (SU) and Saphenous (Saph) nerves were sectioned and
prepared for stimulation. Cord dorsum potentials (CDPs) were recorded in L4-S1 segmental levels.
Intraspinal stimulation was through glass micropipettes filled with NaCl 2 M (0.9 - 2.0 M-Ohms and
tip diameter of 3 - 3.5 m
m) inserted at the site of maximal PAN CDPs. PAD and PAH of PAN single
afferents was inferred from changes in the intraspinal current needed to produce antidromic action
potentials (AAP) with a constant probability (50%). Autogenic stimulation of the PAN nerve were
trains of four stimuli at 700 Hz. Reversible spinal block was made by cooling at T10. Capsaicin (0.3 ml
of 1% solution) was injected into the left plantar pad.

2
95

99 %

CA
Pi

60

ntr
ol

Footpad

Capsaicin

70

nje

Capsaicin
Injection

60 min.

10 xT

Co

80

ol

Saph

95

PAH 100

D
Inflammation

1.5

110

Sp
in

95

PAN

120 min.

140

Sp
in

xT

SP

SU

95

B
m
A

1.5
100

al

Intraspinal Threshold
Change (%)

L7

xT

ntr
ol

PAN

22.3

Co

DRG

Control

PAN

1.5

2.5

100 100

28.8

xT
%

1.2
79

Intraspinal
Stimulator 2

L5

14.3

Ad
artricular afferents develop
capsaicin-induced autogenic PAD

m
A

40

99 %

Saph

Spinal block reduces autogenic PAD induced by intradermic

capsaicin, suggesting activation of descending
mechanisms that limit the action of nociceptive afferents

PAN

AAP

100

ntr

S2

SP

SU

2.4

Co

T10

104

2 min.

1 min.
Control
Unit

98

1.9

Discrim.
S1

100

14.3

xT
%

120 min.

Integrator

Intraspinal
Stimulatior 1

99

99

1.5

PAN

SP

CDPs

REVERSIBLE
SPINAL
BLOCK

10

60 min.

1.7

Intraspinal Threshold
Change (%)

Warm

17.7

200 m
V.

Current to
Voltaje
Converter

Cold

PAN

SP

SU
2

Capsaicin

5
3

SU

1.7

METHODS
2

97

PAN

xT

PAN

SP

The increased autogenic and heterogenic PAD could result from

intrinsic changes in spinal neuronal connectivity as well as from
PAN autogenic stimulation with stimuli 1.2-5xT increased the intraspinal
changes in descending control. An increased autogenic PAD of Ad
threshold (PAH) of a single articular fiber conducting at 45.2 m/s. One
articular afferents would limit the activation induced by nociceptive
hour after the injection of capsaicin the autogenic PAH dissapeared, and
stimulation of the skin and could function as part of a self-regulating
was changed to PAD by two hours after capsaicin. The SP-induced PAD
control of nociceptive information in this pathway.
with pulses 1.2- 5xT was sligthly decreased after capsaicin.

SP

101 99

1.5

11.5

10 min.

The present observations provide evidence that nociceptive

stimulation induced by intradermic capsaicin increases transmission
along the pathways producing autogenic and heterogenic PAD of A,
presumably nociceptive, PAN afferents.

101

Control

2.4

60 min.

Capsaicin

Since at present there is limited information on the type of articular

afferents that express the capsaicin-induced autogenic PAD, we have
now extended these studies and examined PAD of single slow
conducting PAN afferents. PAD was inferred from changes in the
current required for antidromic activation of the intraspinal terminals
of single articular afferents delivered in the region where the PAN
evoked field potentials were largest (L6-L7 segments, 0.6 to 2.2 mm
depth).

The capsaicin-induced autogenic PAD is produced by stimulation of

the PAN nerve fibers with strengths below the peripheral threshold
of the examined articular afferent

PAN

Saph

SP

100 97

2.7

Capsaicin injected into the footpad produced

autogenic PAD in a previously unresponsive
articular fiber

Peripheral Threshold

During the inflammation induced by intradermal

injection of capsaicin, autogenic PAH elicited in a
single articular afferent changes to autogenic PAD

The spinal pathways involved in the generation of autogenetic PAD of articular

afferents have low synaptic effectiveness (dotted lines). The intradermic capsaicin
increases the activity of wide dynamic range spinal neurons receiving synaptic inputs
from cutaneous capsaicin-sensitive afferents (red). Information conveyed by
ascending pathways increases the activity of supraspinal nuclei (blue) and activates
descending pathways acting on dorsal horn neurons. This leads to facilitation of the
spinal circuits involved in the generation of autogenetic PAD.

A, Peripheral threshold vs conduction velocity of

tested afferents. Mean CV 34.2 1.2 m/s, mean
peripheral threshold 2.8 0.3 xT, (n=32). B,
Intraspinal location of threshold measurements.
Black dots location of sites where capsaicin had no
effects on autogenic PAD or PAH.

SUMMARY AND CONCLUSIONS

1.- Stimulation of the posterior articular nerve produced PAH or a
relatively small PAD in single articular afferents.
2.- During the inflammation produced by the intradermic injection of
capsaicin. the autogenic PAH was reduced and changed to autogenic
PAD
3.- After the intradermic injection of Capsaicin, articular afferents
showing small or no autogenic PAD developed a significant autogenic
PAD. This facilitation was mainly observed on A-d
fibers.
4.-Stimuli below threshold of the examined articular afferent also
produced autogenic PAD, suggesting effects induced by activation of
other articular afferents besides the examined fiber.
5.- High spinal block by cooling often reduced the facilitation of the
autogenic PAD and inhibition of PAH induced by capsaicin,
suggesting involvement of supraspinal mechanisms.
6.- It is suggested that the pathways that mediate the autogenic PAD
of articular afferents are facilitated during the state of central
sensitization induced by the intradermic injection of capsaicin. This
facilitation is envisaged as a self-limiting descending mechanism that
prevents excessive activation of second order neurons by increased
nociceptive inputs.
Partly supported by grants NIH NS 09196 & CONACyT 127965.