Biology subjects

Detloff, M. R.

Publications and source records attributed to Detloff, M. R..

4 recordsLinked to original sources

bioRxiv2026

Aberrant Pain Phenotypes Emerge Following Prenatal Hypoxic-Ischemic Injury in a Rabbit Model of Cerebral Palsy

Cerebral Palsy (CP) is the most common motor disability in childhood, and the most frequent comorbidity is pain. Rabbit kits subjected to prenatal hypoxia-ischemia (HI) exhibit allodynia and an expansion of nociceptive afferents in the lumbar spinal cord at postnatal day (P5). In this study, we examined how HI alters the development of multiple sensory modalities and its effect on psychosocial measures and C-fiber distribution in the spinal cord. To do this, we performed an HI surgery to occlude blood flow to fetal New Zealand White rabbits for 40 minutes, or a sham surgery. We performed von Frey, Hargreaves, and a cold allodynia test at P1, P5, P11, and P18. Additionally, we performed open field, a two-texture preference test, and immunofluorescence assays at P18. HI kits exhibit altered development and allodynia in von Frey and Hargreaves and decreased sensitivity to cold. HI kits spend less time on the aversive side of the two-texture preference apparatus and more time in the center of an open field but a higher ratio of that time immobile. This is accompanied by changes in the distribution of C-fibers in the dorsal horn of the cervical and lumbar spinal cord. A principal components analysis revealed prenatal HI produces coordinated alterations across sensory and behavioral domains and multivariate phenotyping captures the overall HI phenotype more comprehensively than any single measure. Overall, HI rabbits kits exhibit altered sensory development, allodynia, anxiety-like behavior, and changes to the distribution of nociceptive afferents in the dorsal horn of the spinal cord.

neuroscience↗

bioRxiv2023

Acute or chronic depletion of macrophages in the dorsal root ganglia induces neuropathic pain after unilateral cervical spinal cord injury in rats

The inflammatory response at the spinal cord injury (SCI) epicenter and heightened macrophage presence in the dorsal root ganglia (DRG) has been well characterized after SCI and correlates with neuropathic pain. CCL2, a chemokine that acts as a macrophage chemoattractant and neuromodulator, is implicated in pain development, however, the role of the CCL2-CCR2 axis in the development of pain after SCI has not been explored. Here, we examined the role of CCL2-CCR2 signaling in macrophage recruitment to the DRG as well as the prolonged presence of macrophages in the DRG on the development and persistence of pain after SCI. Adult female Sprague-Dawley rats received a moderate, unilateral C5 contusion. Sandwich ELISA revealed that CCL2 is upregulated in the ipsilesional C7 and C8 DRGs in the first 24 hours post injury (hpi) and returns to naive levels by 72 hpi. To prevent monocyte-derived macrophage recruitment to the DRG, additional SCI rats received vehicle or INCB3344, a CCR2 antagonist, intravenously at the time of SCI and at 24 and 48 hpi. INCB3344 administration induced transient forepaw allodynia at 7dpi in nearly all rats (88%) compared to only 33% in vehicle controls that resolves partially by 28 dpi, as measured by von Frey and mechanical conflict avoidance paradigms. As expected, qPCR analyses of whole DRG revealed that INCB3344 reduced macrophage markers and inflammatory cytokines in the ipsilesional C7 and C8 DRGs at 7 dpi compared to vehicle treated rats. By 28 dpi, there were no significant differences between INCB3344 or vehicle-treated groups, indicating that SCI-induced macrophage presence in the DRG is delayed by INCB3344 treatment. Moreover, gene expression of markers of macrophage polarity and cytokines suggest a pro-inflammatory environment in the DRG at 28dpi. DRG macrophage ablation via liposomal clodronate at 21dpi did not ameliorate hypersensitive pain behavior, though their ablation did reduce paw withdrawal thresholds in SCI rats that did not previously demonstrate pain behavior. Collectively, these data suggest that driving macrophages to a pro-reparative phenotype may be a viable and effective analgesic strategy that acts by modulating both the immune response and the experience of pain.

neuroscience↗

bioRxiv2021

Enhanced nociception in a rabbit model of cerebral palsy

Spastic cerebral palsy (CP) is a movement disorder marked by hypertonia and hyperreflexia, and the most prevalent comorbidity is pain. Since spinal nociceptive afferents contribute to both the sensation of painful stimuli as well as reflex circuits involved in movement, we investigated the relationship between prenatal hypoxia-ischemia (HI) injury which can cause CP, and possible changes in spinal nociceptive circuitry. To do this, we examined nociceptive afferents and mechanical and thermal sensitivity of New Zealand White rabbit kits after prenatal HI or a sham surgical procedure. As described previously, a range of motor deficits similar to spastic CP was observed in kits born naturally after HI (40 minutes at [~]70-80% gestation). We found that HI caused an expansion of peptidergic afferents (marked by expression of calcitonin gene-related peptide; CGRP) in both the superficial and deep dorsal horn at postnatal day (P)5. Non-peptidergic nociceptive afferent arborization (labeled by isolectin B4; IB4) was unaltered in HI kits but overlap of the two populations (peptidergic and non-peptidergic nociceptors) was increased by HI. Density of glial fibrillary acidic protein (GFAP) was unchanged within spinal white matter regions important in nociceptive transmission at P5. We found that mechanical and thermal nociception was enhanced in HI kits even in the absence of motor deficits. These findings suggest that prenatal HI injury impacts spinal sensory pathways in addition to the more well-established disruptions to descending motor circuits. In conclusion, changes to spinal nociceptive circuitry could disrupt spinalreflexes and contribute to pain experienced by individuals with CP. Significance StatementPerinatal injuries that cause cerebral palsy (CP) typically involve global insults to the central nervous system and are capable of modulating development of both motor and sensory systems. Most individuals with CP experience pain, yet whether nociception is enhanced in this disorder is unexplored. Here, we demonstrate altered topographic distribution of nociceptive afferents in the spinal cord dorsal horn of neonatal rabbits that experienced hypoxic-ischemic (HI) injury in utero; these anatomical changes were associated with nocifensive behavior indicative of pain-like behaviors. Our findings suggest that CP-causative injuries alter spinal sensory pathways (not only descending motor circuits), contributing to increased pain in CP.

neuroscience↗

bioRxiv2020

At-level allodynia after mid-thoracic contusion in the rat

The rat mid-thoracic contusion model has been used to study at-level tactile allodynia after spinal cord injury (SCI), one of the more common types of allodynia. An important advantage of this model is that not all animals develop allodynia and, therefore, it could be used to more clearly examine mechanisms that are strictly related to pain development separately from mechanisms related to the injury itself. However, how to separate those that develop allodynia from those that do not is unclear. The aims of the current study were to identify where allodynia and spasticity develop and use this information to identify metrics that separate animals that develop allodynia from those that do not in order study difference in their behavior. To accomplish these aims, a standardized grid was used to localize pain on the dorsal trunk and map it to thoracic dermatomes, providing for the development of a pain score that relied on supraspinal responses and separated subgroups of animals. Similar to human studies, the development of allodynia often occurred with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of pain phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans who have sustained an SCI. However, the amount of spared spinal matter in the injured cord did not explain the development of allodynia, as was previously reported. This approach can be used to study the mechanism underlying the development of allodynia separately from mechanisms related to the injury alone.

physiology↗