Sensory testing of the skin using heat stimulation In healthy volunteers and neuropathic Pain Patients

Activation of nociceptors (pain sensors) at peripheral sites leads to
trafficking of afferent sensory information to the brain where pain is
perceived as an unpleasant sensation or feeling. The afferent sensory
information undergoes complex modulation at various points of its trajectory,
both at the spinal cord and at higher centers. Modulation at spinal sites is
related to the intrinsic response properties of primary afferent neurons within
the dorsal horn. For example, the response of warm fibers during a 39 oC
stimulus is completely suppressed by cooling pulses greater than 1 oC below 39
oC [1]. Another example is that upon noxious heat stimulation nociceptive
fibers (C- and type IIA-fibers) demonstrate a similar response with an early
peak frequency of discharge at the beginning of the stimulus followed by a slow
adapting response towards low frequency rates at 5 seconds after the onset of
the stimulus [2,3]. Central modulation of pain responses occurs via descending
pathways originating at higher centers in the CNS including the prefrontal
cortex, rostral anterior cingulate cortex (rACC) and insula, which project to
the periaquaductal gray, and rostral ventromedial medulla in the brainstem and
modulate nociceptive input at the level of the dorsal horn [4-6]. The
neurotransmitter involved in this process is noradrenaline that activate the
postsynaptic α2 adrenergic receptor in the dorsal horn. Activation of this
receptor causes profound analgesic responses. Expressions of endogenously
modulated pain responses are placebo- and stress-induced analgesia and
conditioning pain modulation (CPM) [7,8].

We previously tested the paradigm of offset analgesia where a disproportional
large amount of analgesia becomes apparent upon a slight decrease in noxious
heat stimulation, in both healthy volunteers and neuropathic pain patients
[9,10]. This test was abnormal or absent in neuropathic pain patients and
suggests a malfunction of the modulatory process in pain perception, at spinal
or supraspinal sites. Offset analgesia (see below, Fig 2A) is a very short test
that gives valuable information but that does not allow discrimination between
peripheral or central sites. Furthermore, due to its short temporal profile, no
information is obtained of longer stimulation of sensory neurons.

In the current protocol we will perform a variety of sensory tests of the skin
and measure the pain response of patients and healthy volunteers. The aim of
the study is (1) observational, i.e., to assess and describe the responses of
patients and volunteers to a variety of different stimulation paradigms; (2)
diagnostic, i.e., to assess whether specific tests are possibly diagnostic for
specific pain syndromes; (3) mechanistic, i.e., whether the results of the test
may give us valuable information on the site of modulation (central or
peripheral). The latter is possible by applying specific pharmacological agents
and observed possible changes in the response to the pain stimuli.

The following populations will be studied:
1. Healthy volunteers;
2. Neuropathic pain patients due to (a) Complex Regional Pain Syndrome, (b)
Diabetic neuropathy, (c) Sarcoidosis, (d) Ischemic events in spinal cord or
brain; (e) Fibromyalgia.

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