European Journal of Pharmacology 922 (2022) 174872

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Analgesia and pain: Dual effect of dopamine on the peripheral nociceptive

system is dependent on D2-or D1–like receptor activation
B.F.G. Queiroz , F.C.S. Fonseca , R.C.M. Ferreira , T.R.L. Romero , A.C. Perez , I.D.G. Duarte *
Department of Pharmacology, Federal University of Minas Gerais (UFMG), Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: In this study, a pharmacological approach, together with the paw pressure test, was used to investigate the role of
Dopamine dopamine and its receptors in the peripheral processing of the nociceptive response in mice. Initially, the
Antinociception administration of dopamine (5, 20, and 80 ng/paw) in the hind paw of male Swiss mice (30–40 g) promoted
Pain
antinociceptive effects in a dose-dependent manner. This was considered a peripheral effect, as it did not produce
Dopaminergic receptors
changes in the nociceptive threshold of the contralateral paw. The D2, D3, and D4 dopamine receptor antagonists
remoxipride (4 μg/paw), U99194 (16 μg/paw), and L-745,870 (16 μg/paw), respectively, reversed the
dopamine-mediated antinociception in mice with PGE2-induced hyperalgesia. The D1 and D5 dopamine receptor
antagonists SKF 83566 (2 μg/paw) and SCH 23390 (1.6 μg/paw), respectively, did not alter dopamine anti­
nociception. In contrast, dopamine at higher doses (0.1, 1, and 10 μg/paw) caused hyperalgesia in the animals,
and the D1 and D5 receptor antagonists reversed this pronociceptive effect (10 μg/paw), whereas the D2 receptor
antagonist remoxipride did not. Our data suggest that dopamine has a dual effect that depends on the dose, as it
causes peripheral antinociceptive effects at small doses via the activation of D2-like receptors and nociceptive
effects at higher doses via the activation of D1-like receptors.

1. Introduction Romero et al., 2018).

Pain, defined as an unpleasant sensory and emotional experience
that is associated with or similar to that associated with actual or po­
tential tissue injury, is a complex sensation (IASP, 2020). Although it is
important in the self-defence process, when it is persistent or exacer­
bated, pain can compromise organs and systems, leading to tissue
dysfunction (Riedel and Neeck, 2001). In other words, its modulation by
endogenous mechanisms has been widely studied with the aim of better
understanding the events involved in the pain process and thus
combating it (Le Bars, 2002; Millan, 2002; Mason, 2005; Yarnitsky,
2015). Several endogenous molecules with well-described physiological
functions have been proven to be efficient in controlling nociception.
Monoamines, such as serotonin and norepinephrine, are important in
motor control, mood, and behaviour (Schildkraut and Kety, 1967). In
addition to these classic effects, they are involved in pain control,
inhibiting or facilitating pain transmission in the spinal and supraspinal
regions (Suzuki et al., 2004; Pertovaara, 2006). Furthermore, studies
have demonstrated the participation of these neurotransmitters in
antinociceptive functions at the peripheral level (Diniz et al., 2015;
Dopamine, another type of monoamine, is a neurotransmitter widely
known for its role in motor activity (Harrington et al., 1996), regulation
of cognitive functions (Ott and Nieder, 2019), and modulation of
reward-related motivational functions (Schultz, 1998; Berridge and
Kringelbach, 2008; Klein et al., 2018). Furthermore, its involvement in
pain modulation in the supraspinatus regions has already been demon­
strated (Wood, 2008). In the basal ganglia, the activation of dopami­
nergic neurones that project into the ventral striatum/nucleus
accumbens produces analgesia (Altier and Stewart, 1999). Likewise, the
stimulation of A11 cells of the periventricular posterior hypothalamus
led to a reduction in the sensation of pain (Puopolo, 2019). This effect is
related to the activation of dopaminergic D2-like receptors (Fleet­
wood-Walker et al., 1988). Additionally, this group of cells is considered
the main source of descending dopaminergic innervation (Paulus and
Trenkwalder, 2006) and is involved in antinociception induced by
dopamine at the level of the spinal cord (Millan, 2002; Benarroch,
2008).
The type of dopaminergic receptor activation is closely related to the
role that monoamines have in nociception. Five types of receptors,

* Corresponding author. Department of Pharmacology, ICB-UFMG, Av. Antônio Carlos, 6627 – Pampulha Campus, Belo Horizonte, MG, 31270-100, Brazil.
E-mail address: dimitri@icb.ufmg.br (I.D.G. Duarte).

https://doi.org/10.1016/j.ejphar.2022.174872
Received 17 December 2021; Received in revised form 24 February 2022; Accepted 7 March 2022
Available online 14 March 2022
0014-2999/© 2022 Elsevier B.V. All rights reserved.
B.F.G. Queiroz et al. European Journal of Pharmacology 922 (2022) 174872

which are subdivided into two families, have been described (Cools and Casarrubea et al., 2006; Diniz et al., 2018).
Van Rossum, 1976). The D1-like family corresponds to the dopaminergic
receptors D1 and D5. These are responsible for promoting increased 2.4. Experimental protocol
levels of intracellular messenger cyclic adenosine monophosphate
(cAMP), which is involved in the regulation of several physiological PGE2 was administered at zero hour, after measuring the basal
processes. In contrast, the D2, D3, and D4 receptors, which belong to the threshold of the animals. To assess its antinociceptive effect, dopamine
D2-like receptor family, bind to the Gi/G0 protein and reduce cAMP was administered in 170 min and after 180 min, nociceptive threshold
levels. Thus, the activation of D2-like receptors inhibits cell excitability, measurements were taken. To assess the participation of dopaminergic
while the activation of D1-like receptors increases neuronal activity receptors, PGE2 was administered at zero hour, Remoxipride was given
(Kebabian and Calne, 1979; Missale et al., 1998). in 135 min. SKF 83566, U 99194, L-745,870, and SCH 23390 were
At the peripheral level, few studies have related the dopaminergic administered in 160 min. Dopamine was administered in 165 min and in
system to nociception or antinociception. Therefore, in this study, we 180 min the nociceptive threshold was measured. To exclude the sys­
used a combined pharmacological approach to remove the paw sub­ temic effect, PGE2 was administered to both hind paws at hour zero. In
jected to blunt pressure to assess the effect of peripherally injected 165 min, dopamine was administered in the right and saline in the left
dopamine on the nociceptive threshold and to investigate the partici­ paw. The nociceptive threshold was measured in 180 min in both paws.
pation of different types of dopaminergic receptors in this event. Regarding the evaluation of its hyperalgesic effect, dopamine was
administered at hour zero, and measurements were taken every 5 min.
2. Materials and methods
2.5. Statistical analysis
2.1. Animals
The GraphPad Prism 8.00 program was used for statistical analysis of
Male Swiss mice weighing 30–40g were used at the Bioterism Center the data obtained. The results were expressed by means of ±standard
of the Federal University of Minas Gerais. The animals were kept at error (E.P.M.) for each experimental protocol. The data were submitted
controlled temperature (23 ± 2 ◦ C), in a light/dark cycle of 12 h
to one-way variance analysis (for temporal development analysis) or
(6:00–18:00 h), and free access to food and water. After the tests, the two-way followed by bonferroni post-test for multiple comparations.
animals were euthanized by high-dose intraperitoneal injection of
Only p values lower than 0.05 were considered statistically significant.
anesthetic (300 mg/kg ketamine hydrochloride and 15 mg/kg of xyla­
zine hydrochloride, both Sigma-Aldrich, USA). The project was
3. Results
approved by the Ethics Committee on Animal Experimentation under
protocol number 196/2018.
3.1. Antinociception induced by intraplantar low-dose dopamine
administration in animals with PGE2-induced hyperalgesia
2.2. Measurement of nociceptive threshold
Intraplantar dopamine administration (5, 20, and 80 ng/paw) for
Hyperalgesia was induced in animals through intraplantar adminis­
170 min and 10 min before the peak hyperalgesic action of PGE2 (2 μg/
tration of PGE2 (2 μg/paw), and the nociceptive threshold was measured
paw) promoted an antinociceptive effect in a dose-dependent manner.
by the mechanical paw pressure test submitted to blunt pressure (Ran­
The peak of this effect occurred at 185 min and 15 min after the
dall and Selitto, 1957; Kawabata et al., 1992). The test consists of
administration of dopamine (Fig. 1). The dose of 80 ng/paw produced
placing the animal’s paw on the analgesimeter apparatus (Ugo-Basile,
the maximum effect, completely reversing hyperalgesia, but the absence
Italy), with the plantar surface facing the conical part of the device,
of a hyperalgesic stimulus (PGE2) did not significantly alter the basal
which will produce a uniformly increasing pressure on the animal’s paw.
nociceptive threshold of the animals. Fig. 2A shows the Δ of the noci­
The pressure intensity, recorded in grams, which causes a paw with­
ceptive threshold for each dose of dopamine (5, 20, and 80 ng/paw). Δ
drawal reaction is defined as the mechanical nociceptive threshold. A
represents the difference between the mean nociceptive threshold ob­
cut-off value of 150 g was used to avoid possible damage to the tissues of
tained before any injection (time zero) and the mean threshold
the animals’ paws. The threshold value used was the arithmetic mean of
measured at the peak of action of the drugs (see Fig. 3).
three consecutive measurements. The Δ of the nociceptive threshold was
calculated by the difference between the basal measurement (before the
administration of any drug) and the measurement of the animal’s
response to the drugs used.

2.3. Drugs

Prostaglandin E2 (PGE2) (Sigma, USA) was dissolved in ethanol and

before injections it was diluted in saline solution (0.9% NaCl), obtaining
10% ethanol concentration in saline. All other drugs used [Dopamine
hydrochloride (Sigma); the receptor antagonist D1 SKF 83566 hydro­
bromide (Tocris, USA); the receptor antagonist D2 Remoxipride hydro­
chloride (Tocris); the receptor antagonist D3 U 99194 maleate (Tocris);
the receptor antagonist D4 L-745,870 trihydrochloride (Tocris), and the
receptor antagonist D1-D5 SCH 23390 (Tocris)] were dissolved and
Fig. 1. Time-response curve of intraplantar dopamine administration in mice
diluted in saline solution (0.9% NaCl). The drugs were administered
with hyperalgesia induced by PGE2. PGE2 (2μg/paw) and dopamine (5, 20, and
subcutaneously on the plantar surface of the right hind paw of the mice,
80 ng/paw) were administered on the right hind paw in 0h and 170 min,
in volume of 20 μL/paw. Except for the exclusion of the systemic effect respectively. The measurements were performed at intervals of 10 min from
of dopamine, in which PGE2 (2 μg/paw) was administered on both hind 180min (diagram in the graph). Each symbol represents the mean ± E.P.M. of
legs. The dose of each drug used in this study was obtained through pilot the nociceptive threshold in grams (g) for 5 mice per group. *p < 0.05 repre­
experiments and literature data (Nakamura and Ferreira, 1987; Cunha sents a statistically significant difference compared to group PGE2 2 μg + Sal.
et al., 1991; Main et al., 1995; Silva et al., 2001; Mamiya et al., 2004; Control group: Ethanol 10% + Sal. Sal = saline 0.9%; DA = dopamine.

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B.F.G. Queiroz et al. European Journal of Pharmacology 922 (2022) 174872

Fig. 2. (A) Dose-response curve of intraplantar dopamine administration in

mice with hyperalgesia induced by PGE2: PGE2 (2μg/paw) and dopamine (5,
20, and 80 ng/paw) were administered on the right hind paw in 0h and 165
min, respectively. Measurements were performed in 180 min. (B) Exclusion of
the systemic antinociceptive effect of intraplantar dopamine administra­
tion: PGE2 (2μg/paw) was administered on both hind legs, in two groups of
animals (control and test), at time zero. In 165 min dopamine (80 ng/paw) it
was administered only in the right hind paw of the test group animals, while
their vehicle (Sal) was administered to the left hind paw. The animals of the
control group received PGE2 on both hind legs at time zero, and saline in 165
min. Measurements were performed on both hind legs in 180 min. Each column Fig. 3. Effect of D1-like receptor antagonists on dopamine-mediated peripheral
represents the mean ± E.P.M. Δ of the nociceptive threshold in grams (g) for 5 antinociception against PGE2-induced hyperalgesia. PGE2 (2 μg/paw) was
mice per group. *p < 0.05 represents a statistically significant difference administered at time zero. (A) SKF 83566 (2 μg/paw) D1 receptor antagonist
compared to the PGE2 2 μg + Sal groups. R-paw = right paw; L-paw = left paw. and (B) SCH 23390 (1.6 μg/paw) D1-D5 receptor antagonist were administered
Sal = saline 0.9%; DA = dopamine. over 160 min. Dopamine (80 ng/paw) was administered in 165 min. Mea­
surements were performed in 180 min. Each column represents the mean ± E.P.
To exclude the possibility of a systemic effect, PGE2 (2 μg/paw) was M. Δ of the nociceptive threshold in grams (g) for 5 mice per group. *p < 0.05
represents a statistically significant difference compared to column PGE2 2 μg
administered to both hind legs of the animals, and dopamine (80 ng/
+ Sal + Sal. N.S. = statistically non-significant difference; Sal = saline 0.9%;
paw) was injected into the right paw and saline into the left paw. The
DA = dopamine.
nociceptive threshold was measured in both hind legs. Fig. 2B shows
that the antinociceptive effect of the 80 ng/paw dose is restricted only to
dopamine (80 ng/paw), and the nociceptive threshold was measured.
the paw in which it was administered, promoting effect only locally,
SKF 83566 (2 μg/paw), a D1 receptor antagonist, and SCH 23390 (1.6
without the participation of central pathways in this event, in accor­
dance with our objective of evaluating the mechanisms of action only at
μg/paw), a D1–D5 receptor antagonist, did not change the nociceptive
threshold of the animals (Fig. 3AB). Conversely, remoxipride (Remo; 1,
the peripheral level.
2, and 4 μg/paw), a D2 receptor antagonist, completely reversed
dopamine-mediated antinociception (Fig. 4A). Antagonists of the D3 and
3.2. Involvement of D2-like receptors in dopamine-mediated peripheral D4 dopaminergic receptors, U 99194 (2, 4, 8, 16, and 32 μg/paw) and L-
antinociception 745,870 (4, 8, 16, and 32 μg/paw), respectively, partially reversed
antinociception, even when twice the maximum dose was administered
After establishing the dose of dopamine (80 ng/paw) that promotes (Fig. 4BC).
total reversal of PGE2-induced hyperalgesia and the time when this ef­
fect peaked (15 min after administration), the participation of dopa­
minergic receptors was evaluated. Antagonists of these receptors were
administered to animals initially sensitised with PGE2 and treated with

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B.F.G. Queiroz et al.
Fig. 4. Effect of dopaminergic receptor antagonists on dopamine-mediated peripheral antinociception against PGE2-induced hyperalgesia. PGE2 (2 μg/paw) was
administered at 0 min, (A) Remoxipride (1, 2, and 4 μg/paw) at 135 min, (B) U 99194 (2, 4, 8, 16, and 32 μg/paw) or (C) L-745,870 (4, 8, 16, and 32 μg/paw) at 160
min, and dopamine (80 ng/paw) at 165 min. Measurements were performed in 180 min. Each column represents the mean ± E.P.M. Δ of the nociceptive threshold in
grams (g) for 5 mice per group. *p < 0.05 represents a statistically significant difference compared to column PGE2 2 μg + Sal + Sal. #p < 0.05 represents a
statistically significant difference compared to column PGE2 2 μg + Sal + DA 80 ng. N.S. = statistically non-significant difference; Sal = saline 0.9%; DA = dopamine;
Remo = Remoxipride.
3.3. Nociception induced by intraplantar administration of high doses of
dopamine
The next step was to verify whether high doses of this neurotrans­
mitter could induce nociception. For this, dopamine at 0.1, 1, and 10 μg/
paw was administered at zero hour in the right paw of the animals, and
the nociceptive threshold was measured. As noted in Fig. 5, dopamine
promoted a hyperalgesic effect, causing a decrease in the nociceptive
threshold of animals compared to the control group that received
vehicle (saline). This effect was dose-dependent, with a peak observed
within 5 min of administration.
3.4. Participation of D1-like receptors in dopamine-induced nociception
After demonstrating that the D1 family dopaminergic receptors do
not participate in the antinociceptive effect of dopamine, we aimed to
evaluate the participation of these receptors in the nociceptive activity
of this amine. For this, we administered SKF 83566 (0.5, 1, and 2 μg/
paw) and SCH 23390 (0.4, 0.8, and 1.6 μg/paw) in animals pre-treated
with the dose of dopamine that causes nociception (10 μg/paw). After
measuring the nociceptive threshold, we observed that these antagonists
promoted nociception reversal in a dose-dependent manner (Fig. 6AB).
Contrary to D1-like receptors, the selective D2 receptor antagonist
Fig. 5. Time-response curve of the intraplantar administration of a hyper­
algesic doses of dopamine: Dopamine (0.1, 1, and 10 μg/paw) was administered
in the right hind paw at time zero. Measurements were taken at 5-min intervals
(chart diagram). Each symbol represents the mean ± S.E.M. of the nociceptive
threshold in grams (g) for 5 mice per group. *p < 0.05 represents a statistically
significant difference compared to the control group that received only sal. Sal
= saline 0,9%; DA = dopamine.
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European Journal of Pharmacology 922 (2022) 174872
remoxipride was not able to reverse the nociception mediated by
dopamine (Fig. 6C).
All antagonists used to assess the participation of dopaminergic re­
ceptors did not promote nociceptive or antinociceptive activity when
administered alone with PGE2 or vehicle (10% ethanol), a set of results
to the right of each graph.
4. Discussion
Although the involvement of the dopaminergic system in nociception
at the central nervous system level has been well-documented over the
years, there is a lack of studies that show the antinociceptive effect of
dopamine at the peripheral level. In the present study, we investigated
the participation of this monoamine in pain control at the peripheral
level, demonstrating which dopaminergic receptors are involved in this
process. For this purpose, we used a purely pharmacological approach
through the paw pressure test in animals that had increased pain
sensitivity by the administration of a hyperalgesic, PGE2, at a dose that
promotes maximum hyperalgesia (2 μg/paw) (Diniz et al., 2018; Fer­
reira et al., 2019). Its ability to directly sensitise nociceptors without
requiring the participation of intermediate cells is advantageous over
other types of hyperalgesic agents (Cesare and McNaughton, 1997;
Moriyama et al., 2005). In our results, we observed that dopamine (5,
20, and 80 ng/paw) was able to reverse hyperalgesia induced by PGE2,
peripherally, thus suggesting its antinociceptive effect. The maximum
dose (80 ng/paw) completely reversed hyperalgesia, returning the
nociceptive threshold of the animals to basal levels, and generated a
local effect only, with no participation of systemic pathways.
The participation of dopaminergic receptors in the event of periph­
eral antinociception of dopamine was also evaluated. There are five
different types of dopamine receptors (Missale et al., 1998; Vallone
et al., 2000), which are grouped into two families according to their
interaction with the enzyme adenylate cyclase. Thus, the role of dopa­
mine in nociception varies according to the subtype of activated re­
ceptors. D2-like receptors have the ability to reduce neuronal
excitability and are therefore constantly related to antinociceptive ac­
tivity. In 2019, Liu et al. demonstrated that D2-like receptors mediate
the antinociceptive effect produced by the descending dopaminergic
pathway in a trigeminal neuropathic pain model. In addition to this
study, there are reports (Rooney and Sewell, 1989; Zarrindast and
Moghaddampour, 1989) that D2 agonists potentiate opioid
antinociception.
D1-like receptors promote an increase in neuronal excitability and
B.F.G. Queiroz et al.
Fig. 6. Effect of dopaminergic receptor antagonists against dopamine-induced hyperalgesia. (A) SKF 83566 (0.5, 1, and 2 μg/paw) or (B) SCH 23390 (0.4, 0.8, and
1.6 μg/paw) and dopamine (10 μg/paw) were administered to the right hind paw of mice at 0 and 5 min, respectively. Measurements were performed in 10 min. (C)
Remoxipride (4 μg/paw) and dopamine (10 μg/paw) were administered to the right hind paw of mice at 0 and 30 min, respectively. Measurements were performed in
35 min. Each column represents the mean ± S.E.M. Δ of the nociceptive threshold in grams (g) for 5 mice per group. *p < 0.05 represents a statistically significant
difference compared to column DA 10 μg + Sal. N.S. = statistically non-significant difference; Sal = saline 0.9%; DA = dopamine.
are related to the pronociceptive effect induced by dopamine. Results of
previous studies show that the administration of D1-like receptor ago­
nists induces hyperalgesia and potentiates the release of inflammatory
mediators, such as CGRP and substance P, by primary afferent fibres,
transmitting nociceptive messages within the dorsal horn of the spinal
cord (Rooney and Sewell, 1989; Bourgoin et al., 1993). In addition,
when administered peripherally, D1-like receptor antagonists are effi­
cient in reversion of carrageenan-induced hyperalgesia (Nakamura and
Ferreira, 1987) and acetic acid-induced pain (Duarte et al., 1988). To
investigate the effect of D1-like receptors on antinociception at the pe­
ripheral level, we used D1 and D5 receptor antagonists SKF83566 and
SCH 23390, respectively. The two antagonists were not able to alter the
nociceptive threshold of the animals after the administration of dopa­
mine. Our results were in line with those of the previous studies that
demonstrated the participation of D1-like receptors not in anti­
nociception, but in ad-induced hyperalgesia.
In our results, contrary to D2-like receptors, the selective D2 receptor
antagonist remoxipride was able to fully reverse the antinociception
mediated by dopamine, suggesting the participation of these receptors
in cases of peripheral antinociception. The selective D3 and D4 receptor
antagonists U 99194 and L-745,870, respectively, also reversed the
antinociception mediated by dopamine, but only partially, even with the
administration of twice the maximum dose. This event suggests differ­
ences in intracellular signalling mediated by each type of receptor, such
as the level of inhibition of the adenylate cyclase enzyme. For example,
D3 receptors do not or weakly inhibit adenylate cyclase enzyme,
depending on the type of cell line evaluated, as reported in some pre­
vious studies (Chio et al., 1994; Freedman et al., 1994; MacKenzie et al.,
1994; Tang et al., 1994; Robinson and Caron, 1996).
Although dopamine D1-like receptors are expressed in greater
quantities than D2-like receptors, these have high affinity and are acti­
vated by lower concentrations of dopamine (Paulus and Trenkwalder,
2006). Thus, the effects of dopamine on nociception depend on its local
concentration because low levels of dopamine can activate D2-like
antinociceptive receptors, while high levels can activate D1-like pro­
nociceptive receptors (Millan, 2002; Benarroch, 2008). Thus, high
dopamine connections assess the pronociceptive effect of this mono­
amine in the periphery. Dopamine (0.1, 1, and 10 μg/paw) promoted the
hyperalgesic effect in a dose-dependent manner, and when dopamine D1
and D5 receptor antagonists (SKF 83566 and SCH 23390) were admin­
istered, we observed reversal of hyperalgesia induced by the maximum
dose of dopamine (10 μg/paw). Dopamine-induced hyperalgesia was not
inhibited by remoxipride. As expected, these results demonstrate that
high doses of dopamine promote the activation of D1 family dopamine
receptors.
It has been shown that multiple dopamine receptors are expressed in
5
European Journal of Pharmacology 922 (2022) 174872
dorsal root ganglion (DRG) neurones in rats (Xie et al., 1998). A sub­
population of DRG neurones expresses tyrosine hydroxylase, the rate-
limiting enzyme in the synthesis of dopamine (Price and Mudge,
1983). mRNAs and alternatively spliced transcripts of dopamine re­
ceptors have been detected in peripheral sensory neurones (Brumovsky
et al., 2006). The expression of dopamine receptors in DRG neurones has
been confirmed by immunofluorescence imaging (Brumovsky et al.,
2012).
A recent study characterised the expression of dopamine D1 and D5
receptors in DRG neurones by Western blot and immunohistochemical
analysis. The expression of dopamine receptors is limited to small
diameter DRG neurones, which mainly represent nociceptive sensory
neurones (Galbavy et al., 2013). Functional evidence of dopaminergic
receptors in DRG has also been published, and this focuses on the
excitatory or inhibitory effect of dopamine in DRG neurones using
specific D1-or D2-like agonists. The excitatory effect of dopamine is
mediated by D1-like receptor-linked intracellular signalling pathways.
In contrast, the inhibitory effect is mediated by D2-like receptors (Sidhu,
1998; Neve et al., 2004). Based on these reports, we inferred that the
nociceptive effect of dopamine mainly functions in nociceptive sensory
neurones. The possibility of antinociceptive action occurring via
endogenous substance release is open, since there is evidence of the
existence of dopaminergic D2-like receptors in non-neuronal cells such
as keratinocytes and immune cells (Fuziwara et al., 2005; Tóth et al.,
2012), and that our group has demonstrated that dopamine agonist D2
aripiprazole induces peripheral antinociception via release of endoge­
nous opioids (Ferreira et al., 2015).
5. Conclusions
Our study is the first to show that dopamine, when peripherally
administered, is capable of reversing PGE2-induced hyperalgesia, pro­
moting peripheral antinociception. Furthermore, we evaluated each of
the five dopaminergic receptors and thus suggested the participation of
the D2-like dopaminergic receptors in peripheral dopamine-mediated
antinociception and in one of the D1-like receptors in nociception.
These data expand perspectives for new studies related to the dopami­
nergic system in the development of therapeutic strategies that promote
analgesic effects in the periphery.
CRediT authorship contribution statement
B.F.G. Queiroz: Investigation, Methodology, Writing – original
draft. F.C.S. Fonseca: Investigation, Methodology, Writing – original
draft. R.C.M. Ferreira: Methodology. T.R.L. Romero: Investigation,
Resources. A.C. Perez: Resources. I.D.G. Duarte: Investigation,
B.F.G. Queiroz et al. European Journal of Pharmacology 922 (2022) 174872

Resources, Formal analysis, Conceptualization, Writing – review & Galbavy, W., Safaie, E., Rebecchi, M.J., Puolopolo, M., 2013. Inhibition of tetrodotoxin-
resistant sodium current in dorsal root ganglia neurons mediated by D1/D5
editing, Supervision.
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Further reading
Lee, D.W., Cho, P.S., Lee, H.K., Lee, S.H., Jung, S.J., Oh, S.B., 2015. Trans-activation of
TRPV1 by D1R in mouse dorsal root ganglion neurons. Biochem. Biophys. Res.
Commun. 465, 832–837. https://doi.org/10.1016/j.bbrc.2015.08.096.