Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli

112

155

Localized increases in synaptic strength constitute a synaptic basis for learning and memory in the CNS and may also contribute to the maintenance of neuropathic pain after spinal cord injury (SCI) through the de novo formation or elaboration of postsynaptic dendritic structures. To determine whether SCI-induced dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain, we analyzed spine morphometry, localization, and functional influence in dorsal horn (DH) neurons in adult rats 1 month after sham surgery, contusion SCI, and SCI treated with a selective inhibitor of Rac1 activation, NSC23766. After SCI, DH neurons located in lamina IV-V exhibited increased spine density, redistributed spines, and mature spines compared with control neurons, which was associated with enhancement of EPSCs in computer simulations and hyperexcitable responsiveness to innocuous and noxious peripheral stimuli in unit recordings in vivo. SCI animals also exhibited symptoms of tactile allodynia and thermal hyperalgesia. Inhibition of the small GTP-binding protein Rac1 ameliorated post-SCI changes in spine morphology, attenuated injury-induced hyperexcitability of wide-dynamic range neurons, and progressively increased pain thresholds over a 3 d period. This suggests that Rac1 is an important intracellular signaling molecule involved in a spinal dendritic spine pathology associated with chronic neuropathic pain after SCI. Our report provides robust evidence for a novel conceptual bridge between learning and memory on the one hand, and neuropathic pain on the other.

Section: Methodsmentioning

confidence: 99%

Neuropathic Pain Memory Is Maintained by Rac1-Regulated Dendritic Spine Remodeling after Spinal Cord Injury

Tan¹,

Stamboulian²,

Chang³

et al. 2008

112

155

“…After acclimation to the test chamber, thermal hyperalgesia was assessed by measuring the latency of paw withdrawal in response to a radiant heat source (Dirig et al, 1997). Animals were placed in Plexiglas boxes on an elevated glass plate, under which a radiant heat source (4.7 A) was applied to the glabrous surface of the paw through the glass plate.…”

Section: Methodsmentioning

confidence: 99%

Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury

Hains

Saab²,

Klein³

et al. 2004

250

156

Peripheral nerve injury is known to upregulate the rapidly repriming Na v 1.3 sodium channel within first-order spinal sensory neurons. In this study, we hypothesized that (1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na v 1.3, which (2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na v 1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na v 1.3 decreased the expression of Na v 1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that sodium channel expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misexpression of the Na v 1.3 sodium channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.

“…The latency of the hindpaw withdrawal evoked by thermal stimulation was determined using a modified Hargreaves Box (Dirig et al, 1997). In the absence of a response within 20 s, the stimulus was terminated (cutoff time).…”

Section: In Vivo Studiesmentioning

confidence: 99%

Inhibition by Spinal μ- and δ-Opioid Agonists of Afferent-Evoked Substance P Release

Kondo¹,

Marvizón²,

Song³

et al. 2005

116

109

Opioid -and ␦-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. ]-enkephalin (DPDPE) (1 M). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), deliveredat spinal cord segment L2 using intrathecal catheters. These doses of the and ␦ agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.