Wind-up of spinal cord neurones and pain sensation: much ado about something?

Herrero, Juan F.; Laird, Jennifer M.A.; López-García, J.A.

doi:10.1016/s0301-0082(99)00051-9

Cited by 608 publications

(508 citation statements)

References 187 publications

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“…The resolution of these questions will require spinal electrophysiological recordings in Fmr1 KO mice. In addition to LTP and LTD, a shorter-term form of nociceptive sensitization, called wind-up, is normally expressed in the spinal cord and is characterized by a gradual increase in C-fiberevoked spike activity in dorsal horn neurons and their ascending fibers (Baranauskas and Nistri, 1998;Herrero et al, 2000). Our findings demonstrate a clear reduction of wind-up in ascending fibers of the contralateral VLF in Fmr1 KO mice compared with wild-type mice, which adds additional weight to the hypothesis that spinal nociceptive sensitization is decreased in Fmr1 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Price¹,

Rashid²,

Millecamps³

et al. 2007

J. Neurosci.

183

245

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Fragile X mental retardation is caused by silencing of the gene (FMR1) that encodes the RNA-binding protein (FMRP) that influences translation in neurons. A prominent feature of the human disorder is self-injurious behavior, suggesting an abnormality in pain processing. Moreover, FMRP regulates group I metabotropic glutamate receptor (mGluR1/5)-dependent plasticity, which is known to contribute to nociceptive sensitization. We demonstrate here, using the Fmr1 knock-out (KO) mouse, that FMRP plays an important role in pain processing because Fmr1 KO mice showed (1) decreased (ϳ50%) responses to ongoing nociception (phase 2, formalin test), (2) a 3 week delay in the development of peripheral nerve injury-induced allodynia, and (3) a near absence of wind-up responses in ascending sensory fibers after repetitive C-fiber stimulation. We provide evidence that the behavioral deficits are related to a mGluR1/5-and mammalian target of rapamycin (mTOR)-mediated mechanism because (1) spinal mGluR5 antagonism failed to inhibit the second phase of the formalin test, and we observed a marked reduction in nociceptive response to an intrathecal injection of an mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice; (2) peripheral DHPG injection had no effect in KO mice yet evoked thermal hyperalgesia in wild types; and (3) the mTOR inhibitor rapamycin inhibited formalin-and DHPG-induced nociception in wild-type but not Fmr1 KO mice. These experiments show that translation regulation via FMRP and mTOR is an important feature of nociceptive plasticity. These observations also support the hypothesis that the persistence of self-injurious behavior observed in fragile X mental retardation patients could be related to deficits in nociceptive sensitization.

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Section: Discussionmentioning

confidence: 99%

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Price¹,

Rashid²,

Millecamps³

et al. 2007

J. Neurosci.

183

245

View full text Add to dashboard Cite

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“…One of the possibilities for the excitatory effect of SP on the respiratory network is the potentiation of NMDA-mediated processes, as has been described in respiratory-related neurons (Ptak et al, 2000) and other neuronal networks (Liu et al, 1998;Herrero et al, 2000). Therefore, we tested whether SP produced the excitation of the respiratory network after blockade of NMDARs with CPP.…”

Section: Sp-and Nmda-evoked Activitymentioning

confidence: 98%

Substance P-Mediated Modulation of Pacemaker Properties in the Mammalian Respiratory Network

Peña¹,

Ramirez²

2004

J. Neurosci.

141

144

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Neuromodulators are integral parts of a neuronal network, and unraveling how these substances alter neuronal activity is critical for understanding how networks generate patterned activity and, ultimately, behavior. In this study, we examined the cellular mechanisms underlying the excitatory action of substance P (SP) on the respiratory network isolated in spontaneously active transverse slice preparation of mice. SP produced a slow depolarization in all recorded inspiratory pacemaker and non-pacemaker neurons. Ion exchange experiments and blockers for different ion channels suggest that the slow depolarization is caused by the activation of a low-threshold TTX-insensitive cationic current that carries mostly Na ϩ . The SP-induced slow depolarization increased tonic discharge in nonpacemaker neurons and primarily enhanced the frequency of bursting in Cd 2ϩ -insensitive pacemaker neurons. In the Cd 2ϩ -sensitive pacemaker neuron, the burst frequency was not significantly affected, whereas burst duration and amplitude were more enhanced than in Cd 2ϩ -insensitive pacemaker neurons. In a subset of non-pacemaker neurons that produced NMDA-dependent subthreshold oscillations, SP caused the production of bursts of action potentials. We conclude that the degree of pacemaker activity in the respiratory network is not fixed but dynamically regulated by neuromodulators such as SP. This finding may have clinical implications for Rett syndrome in which SP levels along with other neuromodulators are decreased in the brainstem.

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“…TS of "second pain" (TSSP) is considered to reflect 'windup' in DH-neurons and represents a psychophysical model for the study of hyperalgesic mechanisms (Herrero et al, 2000;Sarlani and Greenspan, 2005). Although spinal 'windup' is well established, little is known about the supraspinal representation of this clinically relevant pain mechanism.…”

Section: Introductionmentioning

confidence: 99%

Brain activity related to temporal summation of C-fiber evoked pain

Staud

Craggs

Robinson

et al. 2007

Pain

188

155

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Temporal summation of "second pain" (TSSP) is considered to be the result of C-fiber-evoked responses of dorsal horn neurons, termed 'windup'. This phenomenon is dependent on stimulus frequency (≥ 0.33 Hz) and relevant for central sensitization and chronic pain. Previous brain imaging studies have only been used to characterize neural correlates of second pain but not its temporal summation. We utilized functional magnetic resonance imaging (fMRI) in healthy volunteers to measure brain responses associated with TSSP. Region of interest analysis was used to assess TSSP related brain activation. Eleven pain-free normal subjects underwent fMRI scanning during repetitive heat pulses to the right foot at 0.33 Hz and 0.17 Hz. Stimulus intensities were adjusted to each individual's heat sensitivity to achieve comparable TSSP ratings of moderate pain in all subjects. As predicted, experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. fMRI statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including contralateral thalamus (THAL), S1, bilateral S2, anterior and posterior insula (INS), mid-anterior cingulate cortex (ACC), and supplemental motor areas (SMA). TSSP ratings were significantly correlated with brain activation in somatosensory areas (THAL, S1, left S2), anterior INS, and ACC. These results show that neural responses related to TSSP are evoked in somatosensory processing areas (THAL, S2), as well as in multiple areas that serve other functions related to pain, such as cognition (ACC, PFC), affect (INS, ACC, PAG), premotor activity (SMA, cerebellum), and pain modulation (rostral ACC).

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Wind-up of spinal cord neurones and pain sensation: much ado about something?

Cited by 608 publications

References 187 publications

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Substance P-Mediated Modulation of Pacemaker Properties in the Mammalian Respiratory Network

Brain activity related to temporal summation of C-fiber evoked pain

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