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Galanin-Mediated Behavioural Hyperalgesia from the Dorsomedial Nucleus of the Hypothalamus Involves Two Independent Descending Pronociceptive Pathways.

Amorim D, Viisanen H, Wei H, Almeida A, Pertovaara A, Pinto-Ribeiro F - PLoS ONE (2015)

Bottom Line: Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt), a pronociceptive region projecting to the spinal dorsal horn (SDH) and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R) could relay descending nociceptive facilitation induced by GAL in the DMH.Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i) one relays in the DRt and (ii) the other one involves 5-HT neurones acting on spinal 5HT3Rs.In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.

View Article: PubMed Central - PubMed

Affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.

ABSTRACT
Activation of the dorsomedial nucleus of the hypothalamus (DMH) by galanin (GAL) induces behavioural hyperalgesia. Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt), a pronociceptive region projecting to the spinal dorsal horn (SDH) and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R) could relay descending nociceptive facilitation induced by GAL in the DMH. Heat-evoked paw-withdrawal latency (PWL) and activity of SDH neurones were assessed in monoarthritic (ARTH) and control (SHAM) animals after pharmacological manipulations of the DMH, DRt and spinal cord. The results showed that GAL in the DMH and glutamate in the DRt lead to behavioural hyperalgesia in both SHAM and ARTH animals, which is accompanied particularly by an increase in heat-evoked responses of wide-dynamic range neurons, a group of nociceptive SDH neurones. Facilitation of pain behaviour induced by GAL in the DMH was reversed by lidocaine in the DRt and by ondansetron, a 5HT3R antagonist, in the spinal cord. However, the hyperalgesia induced by glutamate in the DRt was not blocked by spinal ondansetron. In addition, in ARTH but not SHAM animals PWL was increased after lidocaine in the DRt and ondansetron in the spinal cord. Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i) one relays in the DRt and (ii) the other one involves 5-HT neurones acting on spinal 5HT3Rs. In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.

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Behavioural evaluation of paw-withdrawal latencies (PWL) after drug microinjections in the dorsomedial nucleus of the hypothalamus (DMH) and the medullary dorsal reticular nucleus (DRt) of control (SHAM) and arthritic (ARTH) animals.PWL in the contralateral (A) and ipsilateral (B) hind limbs after glutamate (GLU) or lidocaine (LIDO) in the DRt. PWL in the contralateral (C) and ipsilateral (D) hind limbs after galanin (GAL) in the DMH or the combination of GAL in the DMH and LIDO in the DRt. Saline (SAL) injections were used as controls. Graphs show mean PWL + SEM (nSHAM = 7; nARTH = 5). (*P<0.05, **P<0.01: Comparison of the drug effect with the effect of SAL injection in the same experimental group;##P<0.01: Comparison of the effect of drug combination (GAL+LIDO) with the corresponding GAL alone group (t-test with a Bonferroni correction for multiple comparisons).
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pone.0142919.g002: Behavioural evaluation of paw-withdrawal latencies (PWL) after drug microinjections in the dorsomedial nucleus of the hypothalamus (DMH) and the medullary dorsal reticular nucleus (DRt) of control (SHAM) and arthritic (ARTH) animals.PWL in the contralateral (A) and ipsilateral (B) hind limbs after glutamate (GLU) or lidocaine (LIDO) in the DRt. PWL in the contralateral (C) and ipsilateral (D) hind limbs after galanin (GAL) in the DMH or the combination of GAL in the DMH and LIDO in the DRt. Saline (SAL) injections were used as controls. Graphs show mean PWL + SEM (nSHAM = 7; nARTH = 5). (*P<0.05, **P<0.01: Comparison of the drug effect with the effect of SAL injection in the same experimental group;##P<0.01: Comparison of the effect of drug combination (GAL+LIDO) with the corresponding GAL alone group (t-test with a Bonferroni correction for multiple comparisons).

Mentions: To study the phasic and tonic action of the DRt upon nociceptive modulation, PWLs on both contralateral and ipsilateral hind paws were evaluated after injecting GLU, LIDO or SAL in the right (ipsilateral to the inflamed knee joint in the ARTH group) DRt. In the contralateral (left) paw, drug injection in the DRt significantly altered PWL (main effect of drug: F2,20 = 7.388, P = 0.004), although post hoc tests did not indicate any difference between treatment groups (Fig 2A). In the ipsilateral (right) paw, drug injection in the DRt also significantly altered PWL (main effect of drug: F2,20 = 33.001, P<0.001) with post hoc tests indicating that PWL was significantly decreased after DRt activation by GLU in both SHAM and ARTH animals, and increased after DRt inhibition by LIDO in ARTH animals alone (Fig 2B).


Galanin-Mediated Behavioural Hyperalgesia from the Dorsomedial Nucleus of the Hypothalamus Involves Two Independent Descending Pronociceptive Pathways.

Amorim D, Viisanen H, Wei H, Almeida A, Pertovaara A, Pinto-Ribeiro F - PLoS ONE (2015)

Behavioural evaluation of paw-withdrawal latencies (PWL) after drug microinjections in the dorsomedial nucleus of the hypothalamus (DMH) and the medullary dorsal reticular nucleus (DRt) of control (SHAM) and arthritic (ARTH) animals.PWL in the contralateral (A) and ipsilateral (B) hind limbs after glutamate (GLU) or lidocaine (LIDO) in the DRt. PWL in the contralateral (C) and ipsilateral (D) hind limbs after galanin (GAL) in the DMH or the combination of GAL in the DMH and LIDO in the DRt. Saline (SAL) injections were used as controls. Graphs show mean PWL + SEM (nSHAM = 7; nARTH = 5). (*P<0.05, **P<0.01: Comparison of the drug effect with the effect of SAL injection in the same experimental group;##P<0.01: Comparison of the effect of drug combination (GAL+LIDO) with the corresponding GAL alone group (t-test with a Bonferroni correction for multiple comparisons).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643915&req=5

pone.0142919.g002: Behavioural evaluation of paw-withdrawal latencies (PWL) after drug microinjections in the dorsomedial nucleus of the hypothalamus (DMH) and the medullary dorsal reticular nucleus (DRt) of control (SHAM) and arthritic (ARTH) animals.PWL in the contralateral (A) and ipsilateral (B) hind limbs after glutamate (GLU) or lidocaine (LIDO) in the DRt. PWL in the contralateral (C) and ipsilateral (D) hind limbs after galanin (GAL) in the DMH or the combination of GAL in the DMH and LIDO in the DRt. Saline (SAL) injections were used as controls. Graphs show mean PWL + SEM (nSHAM = 7; nARTH = 5). (*P<0.05, **P<0.01: Comparison of the drug effect with the effect of SAL injection in the same experimental group;##P<0.01: Comparison of the effect of drug combination (GAL+LIDO) with the corresponding GAL alone group (t-test with a Bonferroni correction for multiple comparisons).
Mentions: To study the phasic and tonic action of the DRt upon nociceptive modulation, PWLs on both contralateral and ipsilateral hind paws were evaluated after injecting GLU, LIDO or SAL in the right (ipsilateral to the inflamed knee joint in the ARTH group) DRt. In the contralateral (left) paw, drug injection in the DRt significantly altered PWL (main effect of drug: F2,20 = 7.388, P = 0.004), although post hoc tests did not indicate any difference between treatment groups (Fig 2A). In the ipsilateral (right) paw, drug injection in the DRt also significantly altered PWL (main effect of drug: F2,20 = 33.001, P<0.001) with post hoc tests indicating that PWL was significantly decreased after DRt activation by GLU in both SHAM and ARTH animals, and increased after DRt inhibition by LIDO in ARTH animals alone (Fig 2B).

Bottom Line: Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt), a pronociceptive region projecting to the spinal dorsal horn (SDH) and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R) could relay descending nociceptive facilitation induced by GAL in the DMH.Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i) one relays in the DRt and (ii) the other one involves 5-HT neurones acting on spinal 5HT3Rs.In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.

View Article: PubMed Central - PubMed

Affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.

ABSTRACT
Activation of the dorsomedial nucleus of the hypothalamus (DMH) by galanin (GAL) induces behavioural hyperalgesia. Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt), a pronociceptive region projecting to the spinal dorsal horn (SDH) and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R) could relay descending nociceptive facilitation induced by GAL in the DMH. Heat-evoked paw-withdrawal latency (PWL) and activity of SDH neurones were assessed in monoarthritic (ARTH) and control (SHAM) animals after pharmacological manipulations of the DMH, DRt and spinal cord. The results showed that GAL in the DMH and glutamate in the DRt lead to behavioural hyperalgesia in both SHAM and ARTH animals, which is accompanied particularly by an increase in heat-evoked responses of wide-dynamic range neurons, a group of nociceptive SDH neurones. Facilitation of pain behaviour induced by GAL in the DMH was reversed by lidocaine in the DRt and by ondansetron, a 5HT3R antagonist, in the spinal cord. However, the hyperalgesia induced by glutamate in the DRt was not blocked by spinal ondansetron. In addition, in ARTH but not SHAM animals PWL was increased after lidocaine in the DRt and ondansetron in the spinal cord. Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i) one relays in the DRt and (ii) the other one involves 5-HT neurones acting on spinal 5HT3Rs. In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.

Show MeSH
Related in: MedlinePlus