Publicação
Remodeling of medial prefrontal cortex (mPFC) glutamatergic pathways in experimental monoarthritis: role of the ventral mPFC in descending nociceptive modulation
| Resumo: | The understanding of pain mechanisms and the development of novel therapies relies mostly on our knowledge of neurotransmitter pharmacology in nociceptive processing. These neurotransmitter pathways have been extensively characterized at the peripheral nervous system, spinal cord and brainstem levels; however, our knowledge is less comprehensive regarding frontal brain regions. The beginning of the XXI century brought the conventionalization of brain imaging technologies and the uncovering of the major involvement of cortico-limbic structures in pain phenomena. Imaging studies showed that continuous noxious peripheral inputs elicit profound morphological and functional changes in areas such as the prefrontal cortex (PFC), contributing to the emotional and cognitive imbalances occurring in chronic pain. However, contrary to well-studied brainstem pain modulatory areas, such as the rostral ventromedial medulla (RVM) or the dorsal reticular nucleus (DRt), the molecular mechanisms in frontal regions of the brain remain understudied. Hence, we propose to clarify the role of two medial PFC (mPFC) areas, the prelimbic and infralimbic cortices (PL and IL, respectively) towards nociceptive modulation in normal conditions, as well as in prolonged inflammatory pain. The long-term effects of intra-articular injection of kaolin and carrageenan (K/C; four weeks after induction) upon nociceptive behavior and knee joint structure consisted of the development of severe lesions in the articular joint concomitantly to sustained primary hyperalgesia and altered gait. Using a behavioral approach, the tonic and phasic actions of the PL and IL were evaluated in healthy (SHAM, saline intra-articular injection) animals by locally microinjecting lidocaine and glutamate, respectively. This approach uncovered the opposing effects of glutamate in the PL and IL: fast antinociception resulted from PL activation, while slow pronociception resulted from IL activation. The use of metabotropic glutamate receptor (mGluR) agonists and antagonists allowed to dissect the slow effect of glutamate in the IL and to conclude that it acts preferentially upon mGluR5 to facilitate nociception in both SHAM and K/C animals. Interestingly, mGluR5 has no tonic nociceptive input in healthy animals, as observed by the lack of effect of an mGluR5 antagonist. After four weeks of K/C, however, mGluR5 antagonist exerted antinociception, an effect dependent on intact astrocyte function, as shown by the loss of mGluR5 antagonist effect after astrocyte ablation with a specific gliotoxin, L-α-aminoadipate. The contribution of mGluR5 to IL-mediated pronociception was also evaluated by performing electrophysiological recordings of the nociceptive modulatory cells of the RVM and the DRt, as well as in the nociceptive neurons of the spinal dorsal horn. Pronociception from the IL was relayed through the DRt in healthy animals; however, the relay shifted to the RVM after prolonged inflammatory pain. In the dorsal horn, the heat-evoked responses of both wide-dynamic range (WDR) and nociceptive specific (NS) neurons were exacerbated by IL application of mGluR5 agonist in SHAM and K/C animals. Finally, there is also evidence that spinal TRPV1 are possible mediators of IL-induced pronociception. In conclusion, mGluR5 in the IL exacerbates nociceptive behavior, as well as the electrophysiological responses of DRt and spinal nociceptive neurons to peripheral noxious stimulation in rodents. Long-term exposure to inflammatory pain leads to plastic changes in the IL, which promote astrocytic dependent nociceptive modulation and the remodeling of IL-mediated pronociceptive descending pathways from a DRt to a RVM-dependent pathway. Further studies should focus on modulation of the motivational/affective aspects of pain modulation by the IL, for a better understanding of the mechanisms that underlie the development of chronic pain and its associated comorbidities. |
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| Autores principais: | Pereira, Ana Carla David |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | The understanding of pain mechanisms and the development of novel therapies relies mostly on our knowledge of neurotransmitter pharmacology in nociceptive processing. These neurotransmitter pathways have been extensively characterized at the peripheral nervous system, spinal cord and brainstem levels; however, our knowledge is less comprehensive regarding frontal brain regions. The beginning of the XXI century brought the conventionalization of brain imaging technologies and the uncovering of the major involvement of cortico-limbic structures in pain phenomena. Imaging studies showed that continuous noxious peripheral inputs elicit profound morphological and functional changes in areas such as the prefrontal cortex (PFC), contributing to the emotional and cognitive imbalances occurring in chronic pain. However, contrary to well-studied brainstem pain modulatory areas, such as the rostral ventromedial medulla (RVM) or the dorsal reticular nucleus (DRt), the molecular mechanisms in frontal regions of the brain remain understudied. Hence, we propose to clarify the role of two medial PFC (mPFC) areas, the prelimbic and infralimbic cortices (PL and IL, respectively) towards nociceptive modulation in normal conditions, as well as in prolonged inflammatory pain. The long-term effects of intra-articular injection of kaolin and carrageenan (K/C; four weeks after induction) upon nociceptive behavior and knee joint structure consisted of the development of severe lesions in the articular joint concomitantly to sustained primary hyperalgesia and altered gait. Using a behavioral approach, the tonic and phasic actions of the PL and IL were evaluated in healthy (SHAM, saline intra-articular injection) animals by locally microinjecting lidocaine and glutamate, respectively. This approach uncovered the opposing effects of glutamate in the PL and IL: fast antinociception resulted from PL activation, while slow pronociception resulted from IL activation. The use of metabotropic glutamate receptor (mGluR) agonists and antagonists allowed to dissect the slow effect of glutamate in the IL and to conclude that it acts preferentially upon mGluR5 to facilitate nociception in both SHAM and K/C animals. Interestingly, mGluR5 has no tonic nociceptive input in healthy animals, as observed by the lack of effect of an mGluR5 antagonist. After four weeks of K/C, however, mGluR5 antagonist exerted antinociception, an effect dependent on intact astrocyte function, as shown by the loss of mGluR5 antagonist effect after astrocyte ablation with a specific gliotoxin, L-α-aminoadipate. The contribution of mGluR5 to IL-mediated pronociception was also evaluated by performing electrophysiological recordings of the nociceptive modulatory cells of the RVM and the DRt, as well as in the nociceptive neurons of the spinal dorsal horn. Pronociception from the IL was relayed through the DRt in healthy animals; however, the relay shifted to the RVM after prolonged inflammatory pain. In the dorsal horn, the heat-evoked responses of both wide-dynamic range (WDR) and nociceptive specific (NS) neurons were exacerbated by IL application of mGluR5 agonist in SHAM and K/C animals. Finally, there is also evidence that spinal TRPV1 are possible mediators of IL-induced pronociception. In conclusion, mGluR5 in the IL exacerbates nociceptive behavior, as well as the electrophysiological responses of DRt and spinal nociceptive neurons to peripheral noxious stimulation in rodents. Long-term exposure to inflammatory pain leads to plastic changes in the IL, which promote astrocytic dependent nociceptive modulation and the remodeling of IL-mediated pronociceptive descending pathways from a DRt to a RVM-dependent pathway. Further studies should focus on modulation of the motivational/affective aspects of pain modulation by the IL, for a better understanding of the mechanisms that underlie the development of chronic pain and its associated comorbidities. |
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