Pain Inhibits Pain: an Ascending-Descending Pain Modulation Pathway
Linking Mesolimbic and Classical Descending Mechanisms
Glaucia Tobaldini
1
&
Natalia F. Sardi
1
&
Vinicius A. Guilhen
1
&
Luana Fischer
1
Received: 26 November 2017 /Accepted: 11 May 2018
#
Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The ability to modulate pain perception is as critical to survival as pain itself. The most known pain modulation pathway is the
PAG–RVM (periaqueductal gray–rostral ventromedial medulla) descending system. In this study, we hypothesized that it is
functionally linked to the ascending nociceptive control, which is a form of pain-induced analgesia dependent on mesolimbic
mechanisms. To test this hypothesis, we used a pharmacological approach, in which the antinociception induced by noxious
stimulation (forepaw injection of capsaicin) was detected in a standard rat model of inflammatory pain (hindpaw injection of
carrageenan). This antinociception was blocked by interventions known to block the ascending nociceptive control-mediated
analgesia: the blockade of μ-opioid (Cys
2
,Tyr
3
,Orn
5
,Pen
7
amide (CTOP) 0.5 μg) or of dopamine (SCH23390 1.8 μg and
raclopride 5 μg) receptors within the NAc (nucleus accumbens) and that of cholinergic nicotinic receptors (mecamylamine
0.6 μg) within the RVM. The antinociception was also blocked by standard interventions known to block mechanisms of
descending inhibition within either the PAG or the RVM: local acute neuronal blockade (lidocaine 2%), blockade of μ-opioid
receptors (CTOP 0.5 μg), or activation of GABA
A
receptors (muscimol 10 ng). Consistently, interventions that are known to
block spinal mechanisms of descending inhibition also blocked antinociception: lesion of dorsolateral funiculus and the spinal
blockade of serotonergic (WAY100135 46 μgortropisetron10μg) or adrenergic (idazoxan, 50 μg) receptors. Neuronal activity
indirectly estimated by c-Fos expression within the NAc, PAG, and RVM supports behavioral observations. Therefore, this study
provides functional data indicating that noxious stimulation triggers an ascending–descending pain modulation pathway linking
the mesolimbic system to the PAG–RVM descending system.
Keywords Pain modulation
.
Ascending nociceptive control
.
Periaqueductal gray-rostral ventromedial medulla descending
system
.
Mesolimbic system
.
Nucleus accumbens
.
Rat
Introduction
Acute pain is essential for life; it signals potential danger and
draws attention, requiring the individual to engage in recuper-
ative behaviors to avoid further injury. Precisely because of
this, the ability to suppress pain perception is essential to sur-
vival as well. For example, during life-threatening situations,
such as prey–predator confrontations, pain perception should
be suppressed in order to allow a threatened animal to engage
in defensive responses instead of recuperative activities [1]. In
order to achieve this goal, conserved neurobiological mecha-
nisms of pain modulation are recruited leaving the individual
free to express the most advantageous behavior.
Understanding how the brain suppresses pain perception
may contribute not only to understand the essence of adaptive
behavior but also to develop drugs to control one of the
greatest epidemics of mankind: chronic pain, a pathological
kind of pain devoid of biological purpose. In fact, several
drugs already in use for pain management activate pain mod-
ulation mechanisms to induce analgesia [2]. However, we are
still far from efficiently treating persistent pain, and it still
afflicts around 19% of the general population with an
alarming socio-economic burden [3, 4].
Ever since Melzack and Wall published their remarkable
gate control theory of pain [5], we have seen great advances
in our knowledge about pain modulation mechanisms. In the
1970s and 1980s, a series of studies advanced our knowledge
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s12035-018-1116-7) contains supplementary
material, which is available to authorized users.
* Luana Fischer
fischer@ufpr.br
1
Department of Physiology, Division of Biological Sciences, Federal
University of Parana, Curitiba, Parana, Brazil
Molecular Neurobiology
https://doi.org/10.1007/s12035-018-1116-7
@Phil_Robichaud
@deepthiw
@JoseServera