Nucleus accumbens dopaminergic neurotransmission switches its modulatory action in chronification of inflammatory hyperalgesia

Abstract

Dopaminergic neurotransmission in the nucleus accumbens, a central component of the mesolimbic system, has been associated with acute pain modulation. As there is a transition from acute to chronic pain ('chronification'), modulatory structures may be involved in chronic pain development. Thus, this study aimed to elucidate the role of nucleus accumbens dopaminergic neurotransmission in chronification of pain. We used a rat model in which daily subcutaneous injection of prostaglandin E2 in the hindpaw for 14 days induces a long-lasting state of nociceptor sensitization that lasts for at least 30 days following the end of the treatment. Our findings demonstrated that the increase of dopamine in the nucleus accumbens by local administration of GBR12909 (0.5 nmol/0.25 μL), a dopamine reuptake inhibitor, blocked prostaglandin E2 -induced acute hyperalgesia. This blockade was prevented by a dopamine D2 receptor antagonist (raclopride, 10 nmol/0.25 μL) but not changed by a D1 receptor antagonist (SCH23390, 0.5, 3 or 10 nmol/0.25 μL), both co-administered with GBR12909 in the nucleus accumbens. In contrast, the induction of persistent hyperalgesia was facilitated by continuous infusion of GBR12909 in the nucleus accumbens (0.021 nmol/0.5 μL/h) over 7 days of prostaglandin E2 treatment. The development of persistent hyperalgesia was impaired by SCH23390 (0.125 nmol/0.5 μL/h) and raclopride (0.416 nmol/0.5 μL/h), both administered continuously in the nucleus accumbens over 7 days. Taken together, our data suggest that the chronification of pain involves the plasticity of dopaminergic neurotransmission in the nucleus accumbens, which switches its modulatory role from antinociceptive to pronociceptive.

Social defeat stress induces hyperalgesia and increases truncated BDNF isoforms in the nucleus accumbens regardless of the depressive‐like behavior induction in mice

“…Recent data from our group demonstrated that chronic stimulation of the mesolimbic dopaminergic system by intra‐NAc administration of a dopamine reuptake inhibitor facilitated the development of persistent hyperalgesia induced by PGE2 administered in peripheral tissue (Dias et al., ). This study also demonstrated that acute stimulation of the mesolimbic dopaminergic system induces analgesia via dopamine D2 receptor activation, while chronic stimulation of this system may induce plastic changes which lead to persistent hyperalgesia.…”

“…The NAc seems to play an important role in pain modulation (Altier & Stewart, ; Gear, Aley, & Levine, ; Magnusson & Martin, ; Tambeli, Parada, Levine, & Gear, ; Tambeli, Quang, Levine, & Gear, ; Taylor, Joshi, & Uppal, ). Our group recently demonstrated that the NAc has a facilitatory role in persistent inflammatory hyperalgesia that contributes to the chronification of pain in a dependent manner of the dopaminergic neurotransmission (Dias et al., ). Moreover, there is a robust body of evidence indicating the involvement of the dopaminergic mesolimbic system in depressive‐like behavior.…”

Physical Activity Induces Nucleus Accumbens Genes Expression Changes Preventing Chronic Pain Susceptibility Promoted by High-Fat Diet and Sedentary Behavior in Mice

“…Briefly, the original model showed that 14 successive days of intraplantar injection of PGE2 was sufficient to induce persistent hyperalgesia in rodents for more than 30 days after the last PGE2 injection (Ferreira et al, 1990;Villarreal et al, 2009). Here we used a PGE2-induced PH-ST protocol with only seven successive days of intraplantar injection of PGE2, which is not enough to produce persistent hyperalgesia (Ferreira et al, 1990;Dias et al, 2015). Pharmacological studies revealed the role of noninflammatory agents during the hyperalgesia induction, such as PKA (protein kinase A), PKCε (protein kinase C isoform ε), AC (adenylyl cyclase) (Sachs et al, 2009;Villarreal et al, 2009), and NF-κB (nuclear factor kappa-B) (Souza et al, 2015).…”

Physical Activity Induces Nucleus Accumbens Genes Expression Changes Preventing Chronic Pain Susceptibility Promoted by High-Fat Diet and Sedentary Behavior in Mice

“…Briefly, the original model showed that 14 successive days of 10 intraplantar injection of PGE2 was sufficient to induce persistent hyperalgesia in rodents for more 11 than thirty days after the last PGE2 injection (Ferreira et al, 1990;Villarreal et al, 2009). However, 12 here we used a PH-ST protocol with only seven successive days of intraplantar injection of PGE2, 13 which was not enough to produce persistent hyperalgesia (Dias et al, 2015;Ferreira et al, 1990). 14 This model was advantageous compare to others' CP models because further pharmacological studies 15 revealed a key role of non-inflammatory agents in the chronification process, such as PKA (protein 16 kinase A), PKCε (protein kinase C isoform ε), AC (adenylyl cyclase) (Sachs et al, 2009;Villarreal 17 et al, 2009) and NF-κB (nuclear factor kappa-B) (Souza et al, 2015).…”

“…These findings support a study by Song et al (2017) when they found an increase of pain behaviors 22 promoted by an HFD regardless of weight gain. Although the authors found an increased macrophage 23 density in the dorsal root ganglia and increased pain behaviors (Song et al, 2017), they did not 24 investigate any potential effect of an HFD and sedentary behavior in the NAc, a key structure in the 25 CP susceptibility (Dias et al, 2015;Schwartz et al, 2017;Zhang et al, 2019). 26 Furthermore, we reported here that the voluntary PA prevented CP susceptibility promoted by an 27 HFD and sedentary behavior.…”