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Pain Inhibits Pain: an Ascending-Descending Pain Modulation Pathway Linking Mesolimbic and Classical Descending Mechanisms

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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 (Cys2,Tyr3,Orn5,Pen7amide (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 GABAA 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 μg or tropisetron 10 μg) 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.

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Acknowledgments

This study was supported by the National Council for Scientific and Technological Development (CNPq, Brazil), Coordination for the Improvement of Higher Education Personnel (CAPES, Brazil), and Funding Authority for Studies and Projects (FINEP, Brazil). G.T. and N.F.S. were recipient of PhD fellowships from CAPES.

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Authors and Affiliations

  1. Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil

    Glaucia Tobaldini, Natalia F. Sardi, Vinicius A. Guilhen & Luana Fischer

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  1. Glaucia Tobaldini
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  2. Natalia F. Sardi
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  3. Vinicius A. Guilhen
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  4. Luana Fischer
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Correspondence to Luana Fischer.

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Electronic Supplementary Material

Supplementary Table 1

Effect (mean ± S.E.M.) of experimental manipulations on locomotor activity in the open field test. None of the treatments significantly affected locomotion (p > 0.05, one-way ANOVA). N/A = not applicable; vehicle = 0.9% NaCl; NAc = nucleus accumbens; PAG = periaqueductal gray; RVM = rostral ventromedial medulla; DLF = dorsolateral funiculus. (XLSX 11 kb)

Supplementary Figure S1

Capsaicin-induced antinociception is similar to systemic morphine-induced antinociception. The forepaw injection of capsaicin or the systemic morphine administration significantly increased (indicated by the symbol “*”) mechanical nociceptive threshold in animals that have received carrageenan into the hindpaw (repeated-measures ANOVA and Student-Newman-Keuls post hoc test, p < 0.05). The groups 100 μg carrageenan s.c. hindpaw+0.9% NaCl s.c. forepaw and 100 μg carrageenan s.c. hindpaw +250 μg capsaicin s.c. forepaw were replotted from Fig. 2A. (PNG 66.8 kb)

High Resolution (TIF 1.79 mb)

Supplementary Figure S2

Control groups – by themselves the experimental manipulations did not affect carrageenan-induced hyperalgesia. (A) The hindpaw injection of carrageenan dose dependently decreased the mechanical nociceptive threshold. Carrageenan at 20 μg induced an intermediate response which facilitates the observation of any tendency of drugs to further decrease (or increase) mechanical nociceptive threshold (the symbol “#” indicates mechanical nociceptive threshold significantly different from the other groups; the symbol “+” indicates a significant decrease in mechanical nociceptive threshold compared with the saline group,). The administration of the drugs used in this study within the (B) NAc (nucleus accumbens), (C) PAG (periaqueductal gray), (D) RVM (rostral ventromedial medulla) or (E) spinal cord (including DLF lesion) did not affect carrageenan-induced hyperalgesia (repeated-measures ANOVA and Student-Newman-Keuls post hoc test, p < 0.05). (PNG 274 kb)

High Resolution (TIF 4.21 mb)

Supplementary Figure S3

Capsaicin-induced antinociception is similar to intra-PAG DAMGO-induced antinociception. The forepaw injection of capsaicin or the intra-PAG administration of DAMGO (a μ-opioid receptor agonist) significantly increased (indicated by the symbol “*”) mechanical nociceptive threshold in animals that have received saline into the hindpaw (repeated-measures ANOVA and Student-Newman-Keuls post hoc test, p < 0.05). The groups 0.9% NaCl s.c. hindpaw+0.9% NaCl s.c. forepaw and 0.9% NaCl s.c. hindpaw+250 μg capsaicin s.c. forepaw were replotted from Fig. 2A. (PNG 61.4 kb)

High Resolution (TIF 1.78 mb)

Supplementary Figure S4

Microinjection sites. (A) Reconstruction adapted from the atlas of Paxinos and Watson showing microinjections within the NAc core, (B) ventrolateral PAG and (C) RVM. Some symbols overlap others and represent injection sites in two representative groups: “●” on-site injections (animals included in the study); “Δ” off-site injections (animals excluded from the study). Numbers represent distance caudal to bregma in millimeters. (PNG 70.1 kb)

High Resolution (TIF 1.86 mb)

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Tobaldini, G., Sardi, N.F., Guilhen, V.A. et al. Pain Inhibits Pain: an Ascending-Descending Pain Modulation Pathway Linking Mesolimbic and Classical Descending Mechanisms. Mol Neurobiol 56, 1000–1013 (2019). https://doi.org/10.1007/s12035-018-1116-7

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