J Physiol 576.2 (2006) pp 547–556
Spinal dorsal horn neuronal responses to myelinated
versus unmyelinated heat nociceptors and their
modulation by activation of the periaqueductal grey
in the rat
Simon McMullan1and Bridget M. Lumb2
1Hypertension and Stroke Research Laboratory, University of Sydney, Australia
2Department of Physiology, University of Bristol, UK
The aim of this study was to further understand the central processing of inputs arising from
unmyelinated and myelinated nociceptors by (i) determining the response characteristics of
of skin heating to preferentially activate unmyelinated (C-fibre; 2.5◦Cs−1) versus myelinated
neurones encode well only over the first 5◦C above threshold, and that at higher temperatures
responses decline. In contrast, responses to A-nociceptor activation are linear and encode skin
temperature over more than 10◦C, and almost certainly into the tissue-damaging range. PAG
stimulation raised thresholds and decreased significantly the magnitude of responses to A- and
C-nociceptor activation. However, differences were revealed in the effects of descending control
on the relationships between skin temperature and neuronal firing rate; the linear relationship
that occurred over the first 5◦C of slow rates of skin heating was no longer evident, whereas
that to fast rates of skin heating was maintained over the entire range, albeit shifted to the right.
control from the DL/L-PAG. The data are discussed in relation to the role of the DL/L-PAG in
mediating active coping strategies.
(Resubmitted 21 July 2006; accepted after revision 14 August 2006; first published online 17 August 2006)
Corresponding author S. McMullan: Hypertension and Stroke Research Laboratory, Royal North Shore Hospital,
St Leonards, Sydney, NSW 2065, Australia. Email: email@example.com
Information about noxious events in the periphery
is conveyed to the spinal cord in myelinated and
nociceptor convey different qualities of the nociceptive
message, first and second pain, respectively (Raja et al.
1999), and have different roles in animal models of
chronic pain (Fuchs et al. 2000). They have distinct
pharmacological and physiological properties, such as
their conduction velocities and their ability to encode the
et al. 2001), and recent evidence from this laboratory
indicates that they activate distinct central pathways
linking the hypothalamus and midbrain (Lumb et al.
A major determinant of the pain experience is
descending control, which originates from a number
of supraspinal sites and acts to modulate nociceptive
transmission at early stages in pain pathways in the dorsal
horn of the spinal cord (Willis, 1988; Willis & Westlund,
nociceptive reflexes evoked by activity in unmyelinated
(C-fibre) versus myelinated (A-fibre) heat nociceptors:
C-fibre-evoked withdrawal responses to noxious heating
has important implications as neurones in the DL/L-PAG
co-ordinate active coping strategies, of which modulation
to stressors and in emergency situations (Lovick &
Bandler, 2005). One interpretation of this finding is that
C ?2006 The Authors. Journal compilationC ?2006 The Physiological SocietyDOI: 10.1113/jphysiol.2006.117754
548S. McMullan and B. M. Lumb
J Physiol 576.2
distracting information conveyed in C-nociceptors while
preserving the rapidly conducted well-localized aspects of
Given the different roles of unmyelinated and
myelinated nociceptors in normal and pathological pain
the central pathways that they activate, and a selectivity in
their descending control, it is of considerable importance
to gain a better understanding of the spinal processing of
input from these two classes of nociceptor.
To this end, the aims of the current study were twofold:
of dorsal horn neurones.
Experiments were conducted on 18 adult male Wistar
rats (275–300g). All experiments were carried out in
accordance with the UK Animals (Scientific Procedures)
Act, 1986, and associated guidelines. Anaesthesia was
induced with halothane (2–3% in O2), and the trachea,
carotid artery and external jugular vein were cannulated,
Arterial blood pressure and rectal temperature were
monitored and maintained within physiological limits.
During preparatory surgery, anaesthesia was maintained
withdrawal or blood pressure changes.
Preferential activation of myelinated and
unmyelinated heat nociceptors
A heating apparatus that delivered ‘slow’ or ‘fast’ rates
of skin heating to the dorsal hindpaw was used to
preferentially activate unmyelinated (capsaicin-sensitive)
or myelinated (capsaicin-insensitive) heat nociceptors,
respectively (McMullan et al. 2004). The apparatus was
a modified version of that described by Yeomans and
1996), in which slow and fast rates of heating activated
nociceptive primary afferents with conduction velocities
<2.3ms−1(i.e. C-fibres) and >3ms−1(i.e. A-fibres),
respectively. In brief, heat from a sputter-coated projector
bulb was focused onto a thin disk of blackened copper
with the dorsal surface of the skin of the hindpaw. A
was fixed in position between the surface of the copper
disk and the skin, and used to record skin temperature,
which was digitized and captured at 50sampless−1on a
PC running Spike2 version 3.21 (Cambridge Electronic
Design, Cambridge, UK). Using a constant bulb voltage,
fast rates of heating (7.5±1◦Cs−1, measured over 2s
from the start of heating) were used to preferentially
fast and slow ramps, respectively, were rejected. In order
to prevent tissue damage, skin heating was terminated by
a feedback-controlled cut-off device fitted to the power
source. Cut-offs to fast and slow rates of heating were set
at 57 and 55◦C, respectively; data from heating trials in
cut-off value and included in the analysis.
Single-unit dorsal horn recordings
Extracellular single-unit recordings were made from
Class2 (Menetrey et al. 1977) deep dorsal horn
In brief, the vertebrae at each end of a laminectomy
between T13 and L2 were clamped, and a 4% agar pool
was formed over the exposed tissue. To allow access to
the spinal cord, a small window was cut in the agar and
filled with warm mineral oil. The dura were removed,
and extracellular recordings of single unit activity were
made using homemade borosilicate glass microelectrodes
mounted on an active-probe headstage (Intra 767b; WPI,
UK). Electrodes were filled with 4m NaCl and had a
resistance of 4–10M?. The filtered (Neurolog125; low
cut-off, 500–700Hz; high cut-off, 5kHz) and amplified
(Neurolog105; ×1000) signal was monitored on an
oscilloscope, captured by a PC running Spike2 version
also captured as Spike2 ‘Wavemarks’, permitting online
arithmetic plotting of instantaneous firing frequency on a
separate data channel. In some cases multiunit recordings
were made. Wavemarks were used to compare spike shape
at 20kHz) and compared using K-means cluster analysis.
fields of recorded neurones typically extended over an
area equivalent to one quarter of the dorsal surface of the
hindpaw, and were responsive to both low- (e.g. brush)
and high-intensity (e.g. noxious pinch, heating) stimuli.
Only cells that had excitatory receptive fields that were
both accessible to the heater and larger than the copper
disk that formed the heating contact with the skin were
included in the study.
C ?2006 The Authors. Journal compilationC ?2006 The Physiological Society
556 S. McMullan and B. M. Lumb
J Physiol 576.2
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for their assistance. Work was supported by the Wellcome Trust.
S. McM. was a University of Bristol Scholar.
The online version of this paper can be accessed at:
and contains supplemental material consisting of a figure and
legend entitled: Supplementary Fig. 1, Biceps femoris EMG
evoked by slow and fast rates of skin heating (adapted from
McMullan & Lumb, 2006).
This material can also be found as part of the full-text HTML
version available from
C ?2006 The Authors. Journal compilationC ?2006 The Physiological Society