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Proprioceptive Function Is More Sensitive than Motor

Function to Desflurane Anesthesia


Linda S. Barter, MVSc, PhD*
Laurie O. Mark, BA*
Joseph F. Antognini, MD*

BACKGROUND: Evaluating the effects of sub-immobilizing anesthetic doses on movement will identify target neural circuits for investigation as sites of action for
anesthetic-induced immobility.
METHODS: Eleven pithed Northern Leopard frogs received 0, 0.4, 0.8, and 1.2 times
the 50% effective dose for production of immobility (ED50) of desflurane and a
further 7 received 0 and 0.4 ED50 desflurane in random order. An electric stimulus
applied to the forelimb elicited a hindlimb wiping reflex that was captured on
video for later analysis. Isometric tension developed in the hindlimb during the 30 s
stimulus application was measured.
RESULTS: Compared to 0 ED50, 0.4 ED50 desflurane significantly increased latency to
wipe 0.8 (0.1, 4.0) to 17.3 (0.4, 30.0) s (median [min max]), distance traveled by the
hindfoot 0.42 (0.09, 1.82) to 0.89 (0.16, 4.82) m, and proximity of the hindfoot to
stimulus 1 (0, 5) to 7 (1, 40) mm. It did not alter hindlimb maximum velocity or
isometric tension but significantly reduced total hindlimb force 7.3 (1.7, 23.6) to 3.2
(1.4, 13.8) N. s proportionate to a reduced number of movements from 12 (3, 28) to
8 (2, 14). From 0.4 to 0.8 ED50, motor depressant effects of desflurane became
apparent with significant reductions in maximum tension from 2.0 (0.6, 5.5) to 0.8
(0.1, 1.6) N and total force from 3.2 (1.4, 13.8) to 0.9 (0.0, 2.5) N.s.
CONCLUSIONS: Proprioceptive function is more sensitive to anesthetic-induced
depression than motor function in frogs. This suggests that the most anestheticsensitive component of the spinal neural circuitry underlying movement generation in response to noxious stimulus is prior to the level of the motoneuron.
(Anesth Analg 2009;108:86772)

he spinal cord is capable of generating complex


movement patterns. One example is the wiping reflex of
the frog: a noxious stimulus placed on the body surface
is wiped away by a limb. Regardless of stimulus placement or body positioning, a spinal frog is able to
accurately wipe away the noxious stimulus.1
Current evidence suggests that volatile anesthetic action
in the spinal cord is important for the production of
immobility in response to noxious stimulation.2,3 Beyond
this, we do not have a good understanding of where these
drugs may act to produce immobility. Investigating how
stimulus-evoked movement is altered as anesthetic dose is
increased will guide investigation of particular neural circuits as targets for anesthetic-induced immobility.
In rats, increasing the isoflurane dose from 0.6 to 0.9
minimum alveolar anesthetic concentration (MAC)

reduces the number but not the force of movements.4


Further increasing the isoflurane dose from 0.9 to 1.1
MAC reduces the force of movement or abolishes it
altogether. There has been little investigation of the
effects of anesthetics on movement patterns at anesthetic doses below 0.6 MAC.
We hypothesized that proprioception, the ability to
accurately localize parts of the body in space, would
be more sensitive than motor function to depression
by anesthetics. Using the wiping reflex of the frog, we
aimed to examine the dose-dependent effects of desflurane anesthesia on wiping reflex accuracy and
hindlimb motor function.

From the Departments of *Anesthesiology and Pain Medicine,


and the Section of Neurobiology, Physiology and Behavior, University of California, Davis, California.
Accepted for publication September 16, 2008.
Supported by NIH Grant GM 61283 and GM 47818 (to J.F.A.).
Reprints will not be available from the author.
Address correspondence to Linda S. Barter, MVSc, PhD, Department of Veterinary Surgical and Radiological Sciences, 2112 Tupper
Hall, University of California, Davis, CA 95616. Address e-mail to
lsbarter@ucdavis.edu.
Copyright 2009 International Anesthesia Research Society

The animal care and use committee of the University of California, Davis, approved this study. Eighteen adult Northern Leopard frogs (Rana pipiens)
weighing 46.6 14.3 gm (mean sd) were obtained
from a commercial source (Charles Sullivan, Nashville, TN). Frogs were housed in 5 3 2 foot tubs
with free access to water and fed crickets every other
day. The room temperature was maintained between
20 and 21C and a 12:12 h light: dark cycle provided.
After a 4-wk acclimatization period, frogs were pithed
under a combination of hypothermia and desflurane

DOI: 10.1213/ane.0b013e318193eabe

Vol. 108, No. 3, March 2009

METHODS
Animals

867

anesthesia then allowed 24 h to recover. Pithing


resulted in decerebration and was performed by insertion of a needle through the foramen magnum
followed by rapid vertical and horizontal movements
of the needle tip within the cranial vault.

Anesthesia
Anesthetic doses delivered to the frogs were proportions of the 50% effective dose required to produce
immobility (ED50). The ED50 for immobility in frogs
would be an equivalent anesthetic dose to MAC in
mammals. Eleven frogs received 4 treatments: 0, 0.4,
0.8, and 1.2 ED50 desflurane in random order on
consecutive days. At a separate time, an additional 7
frogs received each of 3 treatments: 0, 0.4 ED50 desflurane or 0.4 ED50 isoflurane in random order on consecutive days. Previous studies in Northern hindlimb
frogs determined population ED50 for immobilization
by desflurane to be 6.78% atm at 21C.5 The isoflurane
data were collected as a preliminary investigation and
are not presented in this article.
Desflurane was delivered from a precision vaporizer in oxygen into a 4 L chamber. The gas outlet of the
chamber had a side port for connection of a gas
sampling line via which anesthetic concentration in
the chamber was monitored (Rascall II, DatexOhmeda, Helsinki, Finland). Frogs were placed in the
chamber up to two at a time and an overpressure
technique used to induce anesthesia to the desired
level.5 In brief, frogs were first exposed to twice the
desired desflurane concentration for a period equivalent to 1 equilibration half-life for that anesthetic (42
min) followed by exposure to the desired concentration for a further two half-lives. The 0 ED50 group
received oxygen only for an equivalent period of time.
At the completion of anesthetic exposure, frogs were
briefly removed from the chamber (no longer than 5
min) and had either the wiping reflex or hindlimb force
evaluated. Frogs were then returned to the anesthetic
chamber for a period of one half-life after which they
were removed for evaluation of the wiping reflex or
hindlimb force, whichever had not previously been
tested. The order of evaluating wiping reflex or force
was alternated such that within each treatment group
half of the animals had each tested first. Anesthetic
uptake and elimination in these animals is reliant upon
cutaneous diffusion. As such, anesthetic kinetics are
markedly slower in frogs when compared to mammals.5
In pilot studies, removal from anesthetic for 15 min did
not alter a frogs response to noxious stimulus. Frogs
were allowed at least 18 h to fully recover between
anesthetic exposures.

Wiping Reflex
Frogs were immobilized in ventral recumbency by
a soft material suit that had been secured to a flat,
smooth plastic surface. The suit was secured around
the body of the frog with Velcro straps such that it did
not impede hindlimb movement. Both forelimbs and
868

Effects of Desflurane on Frog Wiping Reflex

one hindlimb were extended and secured with flat


cotton ties. The free hindlimb was positioned with the
hip and knee joints at 90 angles and the tarsus at a 45
angle. A stimulus was delivered to the forelimb ipsilateral to the free hindlimb for 30 s or until physically
removed by the hindlimb. The stimulus was a 0.2 ms
50 Hz 10 mA current (Digi Stim II, Neuro Technology,
Houston, TX) delivered via two wire electrodes placed
on opposing sides of the forelimb. A camera placed
directly above the back of the frog captured the
wiping reflex on video. Video was digitized at 30
frames per second and using a web-based free access
video analysis program (Video analysis on the Web,
http://electron9.phys.utk.edu/video/, M. Breinig and
B. Barker, University of TN, last accessed June 9, 2008)
the position of the hindfoot relative to the stimulus
was recorded for every frame with minimum resolution of 0.6 mm per pixel. An indicator light on the
electric stimulator shone during current delivery and
was included in the camera frame as a reference for
time of application of stimulus. A metric ruler was
positioned on the table surface next to the frog for
distance calibration of the video image. From these
data the following variables were measured: time
from application of the stimulus to first movement of
the hindfoot (latency to move), time from application
of the stimulus to accurate wipe (latency to wipe), and
the shortest distance achieved between the hindfoot
and the stimulus (proximity). An accurate wipe was
defined as the hindlimb moving within a 5 mm radius
of the stimulus. Distance traveled by the hindfoot was
extrapolated by assuming that the foot traveled a
straight line within the horizontal plane between
frames. From that data, the following variables were
calculated: maximum and average velocity of hindfoot
movement, and total distance traveled by the hindfoot
until an accurate wipe was performed or 30 s had
elapsed.

Motor Evaluation
Frogs were secured to a flat plate as described
above. The hindlimb to be tested was fully extended at
an angle 45 to the long axis of the body and an
inflexible plastic band secured firmly around the hock.
A calibrated force transducer, positioned perpendicular to the extended limb and vertically level with the
hock, was secured with nonelastic cotton tape to the
hock band. The force transducer was attached to a
Grass DC amplifier (Grass Instruments, Baintree, MA)
and the output displayed and recorded by a personal
computer using a Chart PowerLab interface and
Chart5 software (ADInstruments, CO Springs, CO).
The stimulus as described above was applied for 30 s
and hindlimb isometric tension measured. Force tracings were analyzed off-line and the following variables measured for the 30 s of stimulus application;
maximum isometric tension (N), total force generated
or impulse (N.s), and number of movements.
ANESTHESIA & ANALGESIA

Table 1. Effects of Desflurane Dose on the Frog Wiping Reflex

Latency to move (s)


Latency to wipe (s)
Average velocity (m/s)
Maximum velocity (m/s)
Proximity to stimulus (mm)
Distance moved (m)
Maximum tension (N)
Impulse (N.s)
Number of movements

0 ED50
n 18

0.4 ED50
n 18

0.8 ED50
n 11

1.2 ED50
n 11

0.2 (0.0, 1.5)


0.8 (0.1, 4.0)
0.4 (0.1, 1.2)
2.9 (0.6, 4.8)
1 (0, 5)
0.42 (0.09, 1.82)
2.1 (0.5, 6.2)
7.3 (1.7, 23.6)
12 (3, 28)

1.5 (0.7, 4.8)*


17.3 (0.4, 30.0)*
0.3 (0.0, 0.6)*
2.1 (0.8, 4.7)
7 (1, 40)*
0.89 (0.16, 4.82)*
2.0 (0.6, 5.5)
3.2 (1.4, 13.8)*
8 (2, 14)*

1.7 (0.8, 3.3)*


30.0 (1.8, 30.0)*
0.1 (0.1, 0.5)*
2.0 (0.6, 3.7)
33 (0, 88)*
0.71 (0.11, 6.61)
0.8 (0.1, 1.6)*
0.9 (0.0, 2.5)*
6 (0, 13)

30.0 (1.5, 30.0)*


30.0 (30.0, 30.0)*
0.0 (0.0, 0.09)*
0.0 (0.0, 2.2)*
146 (33, 161)*
0.00 (0.00, 1.72)*
0.1 (0.0, 0.6)*
0.0 (0.0, 0.6)*
0 (0, 8)*

Eleven Northern Leopard frogs received 0, 0.4, 0.8, and 1.2 ED50 of desflurane.
An electric stimulus applied to the forelimb was used to elicit a hindlimb wiping reflex.
Isometric tension developed in the hindlimb during 30 s application of the same stimulus was measured.
Video analysis of the wiping reflex enabled the position of the hindfoot to be tracked relative to the stimulus.
Parameters reported in Table 1 pertain to the hindfoot over a period of 30 s or until an accurate wipe was performed (foot within 5 mm of stimulus) and are presented as median (min, max).
Within each set of comparisons, significant differences (P 0.05) from 0 are signified by *, from 0.4 ED50 by , and from 0.8 ED50 by .

At completion of the experiment, frogs were euthanized by overdose of tricaine methanosulfonate


(MS222 5 gm/L). Heads were removed and fixed in
10% buffered formalin and later dissected to confirm
complete destruction of forebrain structures.

Statistical Analysis
Summary data are presented as median (min, max).
For the purposes of comparison, frogs that did not
move, or reach within 5 mm of the stimulus, were
allocated a time of 30 s for latency to move, or latency
to wipe, respectively. Data for most parameters, obtained from the 11 frogs tested under all 4 conditions,
were not normally distributed in the 0.8 and 1.2 ED50
groups. At these higher anesthetic doses, an increasing
number of animals did not wipe or move and so
received 0 for the movement parameters or a maximum time of 30 s for the timed parameters. Friedman
test with Dunns multiple comparisons post hoc tests
were used to assess the effect of anesthetic for all
parameters in the 11 frogs. All data sets from the 0 and
0.4 ED50 treatments met criteria for normality, as
assessed by the Kolmogorov-Smirnov test. Data for 0
and 0.4 ED50 treatments for each parameter from the
two groups of frogs tested at different times were
compared using Students t-test. No significant differences were found, so these data were pooled for
further analysis. Paired Students t-test were then used
to compare effect of desflurane dose (0 and 0.4 ED50)
on all parameters. For all analyses, the significance
level was set at P 0.05.

RESULTS
At an anesthetic dose of 0.8 ED50 or lower, all frogs
moved and at 1.2 ED50 1 of 11 frogs moved. In the
absence of anesthesia, all frogs wiped accurately, that
is the hindfoot reached within 5 mm of the stimulus.
The number of frogs accurately wiping decreased with
increasing anesthetic dose. Nine of 18, 2 of 11, and 0 of
11 frogs wiped accurately at 0.4, 0.8, and 1.2 ED50
Vol. 108, No. 3, March 2009

desflurane, respectively. Summary data for all variables are presented in Table 1.
From 0 to 0.4 ED50, significant increases occurred in
latency to move (0.2 [0.0, 1.5] to 1.5 [0.7, 4.8] s), latency
to accurately wipe (0.8 [0.1, 4.0] to 17.3 [0.4, 30.0] s),
proximity to the stimulus (1 [0, 5] to 7 [1, 40] mm), and
distance traveled by the hindfoot (0.42 [0.09, 1.82] to
0.89 [0.16, 4.82] m). Average velocity of hindfoot
movement was reduced (0.4 [0.1, 1.2] to 0.3 [0.0, 0.6]
m/s) while maximum velocity (2.9 [0.6, 4.8] to 2.1 [0.8,
4.7] m/s) and maximum isometric tension (2.1 [0.5,
6.2] to 2.0 [0.6, 5.5] N) were unchanged. Total force
generated was significantly reduced (7.3 [1.7, 23.6] to
3.2 [1.4, 13.8] N.s) in part due to a significant reduction
in the number of movements (12 [3, 28] to 8 [2, 14]).
Increasing the desflurane dose from 0.4 to 0.8 and
from 0.8 to 1.2 ED50 both significantly reduced maximum hindlimb tension from 2.0 (0.6, 5.5) to 0.8 (0.1,
1.6) to 0.1 (0.0, 0.6), respectively. An example of typical
isometric tension tracings recorded from the frog
hindlimb at 0, 0.4, 0.8, and 1.2 ED50 desflurane are
shown in Figure 1.
The minimum distance between the hindfoot and
stimulus (proximity) increased significantly with each
increase in anesthetic dose (Table 1 and Fig. 2). The
path taken by the hindfoot during the wiping reflex
varied with anesthetic dose, with examples of typical
trajectories shown in Figure 2. In the absence of
anesthesia, frogs typically extended the hindlimb followed rapidly by a movement that brought the foot
directly forward to the site of the stimulus and
brushed it laterally away from the body. At 0.4 ED50
desflurane, the first movement was typically forward
towards the stimulus. If the stimulus was not removed
on the first attempt (often the case), the limb was
extended backwards towards its initial position and
the whole movement repeated a further 12 times
before removal of the stimulus or cessation of movement. At 0.8 ED50 desflurane, the first movement of
the foot was directed towards the stimulus typically
2009 International Anesthesia Research Society

869

Figure 1. Representative examples of force tracings from a


pithed Northern Leopard frog after receiving 0, 0.4, 0.8, and
1.2 ED50 desflurane. An electric stimulus was applied to the
forelimb for 30 s and isometric tension development in the
ipsilateral hindlimb recorded by a force transducer positioned perpendicular and level with the extended hindlimb.

Figure 2. Typical examples of the trajectory of the hindfoot


during the wiping reflex in a pithed Northern Leopard frog
in the absence of anesthesia (0) or the same frog after
receiving 0.4 and 0.8 ED50 desflurane. An electric stimulus
on the forelimb (black cross) was used to elicit the reflex that
was captured on video. Analysis of the digitized video
enabled the position of the hindfoot to be tracked in every
frame (closed black circles). For reasons of clarity, where the
position of the hindfoot did not change, a black circle was
not drawn for every frame.

traveling only part of the distance to the stimulus and


then making a series of laterally directed scratching
movements in space (Fig. 2).

DISCUSSION
Movement of anesthetized patients in response to
stimulation is a common indicator of anesthetic depth.
It has also provided a descriptor of anesthetic potency
that has been in common use for more than 40 yr. The
MAC of an anesthetic describes the alveolar anesthetic
870

Effects of Desflurane on Frog Wiping Reflex

concentration, which suppresses movement in 50% of


animals subjected to a supramaximal noxious stimulus.6 The mechanisms by which anesthetics induce
immobility are not known. When evaluating anestheticinduced immobility, the focus has typically been on
the presence or absence of gross movement. There has
been little investigation of the effects of subimmobilizing doses of anesthetics on movement. The
current findings, that accuracy and pattern of movement are more sensitive to depression by desflurane
anesthesia than motor function, suggest that part (or
parts) of the neural circuitry underlying movement
generation in response to noxious stimulation prior to
the level of the motoneuron are most sensitive to
anesthetic depression.
Compared to the anesthetic-free state, 0.4 ED50
desflurane increased latency to wipe, minimum distance (proximity) to stimulus and distance traveled by
the foot. It did not affect the maximum speed of
movement or tension generated by the limb. Total
force generated by the hindlimb was reduced but this
change was partly due to the reduction in number of
movements at 0.4 ED50. It has been reported in rats
that increasing the halothane or isoflurane dose from
0.6 to 0.9 MAC did not significantly depress force per
movement in response to foot clamp but did reduce
the number of movements and, consequently, total
force generated during stimulus application.4 This is
consistent with the current findings, although occurring at a slightly higher dose range. Motor function of
the frogs in this study was depressed at 0.8 and 1.2
ED50 desflurane. Maximum tension and total force
generated by the hindlimb were both reduced. At 0.8
ED50, the reduction in total force was proportionately
greater than the reduction in number of movements.
This is also consistent with the previous report in rats
in which increasing halothane or isoflurane dose from
0.9 to 1.1 MAC depressed force per movement, total
force and number of movements of the extremities of
rats in response to foot clamp.4 The depression of
motor function we describe in frogs occurred at lower
doses than in the study reported by Antognini et al.,4
although in that study, trends towards reduction in
force per movement were seen in the step from 0.6 to
0.9 MAC. Had anesthetic doses lower than 0.6 MAC
been evaluated in that study, a significant change may
have been seen.
It is hypothesized that complex motor patterns,
such as the frog wiping reflex, are constructed by
variably combining small units of motor output controlled by intrinsic spinal neuronal circuits (central
pattern generators or CPG).710 Sensory input to these
CPG circuits plays a role in initiating and modulating
movement.8,1114 Anesthetic depression of sensory afferent input into these CPG circuits or direct effects on
neurons of the CPGs may underlie the reduction in
wiping reflex accuracy and alterations in the pattern of
movement seen in this study.
ANESTHESIA & ANALGESIA

Reduced sensory input is not likely to be the result


of anesthetic effects in the periphery. Volatile anesthetics have been shown to sensitize peripheral nociceptors15,16 and to produce hyperalgesia at low
doses.17,18 In addition, volatile anesthetics do not
affect peripheral nerve conduction.19,20
Many primary sensory afferent neurons synapse
onto neurons in the spinal cord dorsal horn.21,22 The
effect of desflurane on dorsal horn neurons has not
been investigated, however, the effects of other volatile anesthetics on dorsal horn neuronal activity have
been reported. Most studies examine effects of anesthetic doses bracketing the production of immobility,
for example, from 0.8 to 1.2 MAC. In this range,
halothane, but not isoflurane, reduces evoked dorsal
horn neuronal activity.2327 There are fewer reports
describing the effects of these drugs on evoked neuronal responses at lower anesthetic doses. Halothane
delivered at 0.5% to spinal cord transected, decerebrate cats reduced noxious heat-evoked responses
from dorsal horn neurons.28 In decerebrate rats, a
trend towards depression of dorsal horn neuronal
wind-up was seen when either halothane or isoflurane
doses were increased from 0 to 0.4 and from 0.4 to 0.8
MAC.29 These studies provide some evidence that
afferent input into motor circuits may be depressed by
doses of volatile anesthetics in the range of 0.4 ED50.
Afferent input to the spinal cord in the form of
proprioceptive feedback from the wiping limb plays
an important role in trajectory control during the
wiping reflex.30 Our results suggest that the trajectory
of the hindfoot during execution of the wiping reflex is
sensitive to anesthesia. Additionally, reduced or absent proprioceptive feedback may account for the
reduction in accuracy of the wiping reflex seen with
increasing anesthetic dose. Mammalian proprioceptive afferents project to both the dorsal and ventral
horn3134 and populations of spinal neurons are described that respond exclusively to joint manipulation
or deep tissue pressure.35,36 There has been little work
directed specifically at evaluating the effects of general
anesthetics on proprioceptive spinal neurons. Wall35
described severe depression of these neurons in
lamina VI of the cat dorsal horn by pentobarbital.
Deafferentation, which would abolish proprioceptive
feedback, does not result in loss of movement.37
Anesthetics could, however, modulate these neurons
in a manner different from their total removal from
the neural circuit, for example, by altering the balance
of excitatory and inhibitory input that proprioceptive
afferent neurons contribute to the motor circuit.
Volatile anesthetics may have direct depressant
effects on CPG neurons. Isoflurane depresses the
spontaneous firing rate of ventral horn interneurons in
cultured spinal cord slices, suggested to reflect reduced activity of central pattern generating circuits.38
In the lamprey isolated spinal cord, a model for
investigating vertebrate CPGs,39 isoflurane has been
shown to depress the activity of CPG neurons in
Vol. 108, No. 3, March 2009

addition to altering their intersegmental coordination.40 Investigation of the effect of volatile anesthetics
on movement elicited by stimulation of the mesencephalic lomomotor region also suggests immobility is
mediated via an action on ventral horn locomotor
networks.41
Depression of motor function seen at and above 0.8
ED50 desflurane in this study was not likely due to an
effect on peripheral motor apparatus. In humans, both
peripheral motor nerve conduction and neuromuscular transmission are unaffected by doses of desflurane
ranging from 0% to 7.4%.19 Instead, direct, or indirect,
effects on the motoneuron may underlie this phenomenon. Anesthetics have been shown to decrease motoneuron excitability as assessed by H-reflex and
F-wave studies.42 44 However, in neither of these
techniques is investigation restricted to intrinsic properties of the motoneuron. An alteration in the balance
of inhibitory and excitatory input to the motoneuron
would also alter H-reflex and F-wave responses. That
is, although motor function becomes depressed at
higher anesthetic doses, it is conceivable that this is the
result of anesthetic effects more proximally in the
neural circuit, reducing the balance of tonic or evoked
input to the motoneuron.
Frogs attempting to wipe away a noxious stimulus
at a desflurane dose of 0.4 ED50 show reduced accuracy and different patterns of movement without
alteration of the force or speed with which the limb
moves. With increase in desflurane dose to 0.8 ED50,
further reductions in movement accuracy occur in
addition to reduction in the force of movement. We
conclude that in the frog a component of the neural
circuit underlying movement generation proximal to
the motor neuron, such as sensory input or interneurons within CPG circuits, is most sensitive to anestheticinduced depression. Whether motoneurons then
become depressed directly by higher anesthetic doses
or whether the reduction in motor function seen
occurs subsequently to continued depression of neural
structures providing input to motoneurons remains to
be evaluated.
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