Background & Aims
Pain is a common experience of those with cerebral palsy (CP). The etiology of pain in people with CP has been mainly attributed to the characteristics of the movement disorder, the frequent surgical interventions, neurolytic injections and even physical therapy sessions. While CP is identified by the nature and extent of muscle tone abnormality and motor impairments, pain is such a frequent problem it could be considered a feature of the condition. Understanding the genesis and reducing pain is a major focus for improving quality of life in those with CP. The purpose of this study was to validate behavioral assays that evaluate the pain experience in a rabbit model of CP and to assess the anatomical distribution and density of nociceptive fibers within the dorsal horn.
Methods
Male and female New Zealand white rabbits exposed to prenatal hypoxia-ischemia (HI) for 40 minutes at 70-80% gestation, and sham operated control rabbits (which were prenatally exposed to anesthesia but not HI) were assessed throughout postnatal development for several features of the multidimensional pain experience including: paw hypersensitivity using modified von Frey and Hargreaves’ tests, anxiety using the open field test, anhedonia using a modified sucrose preference test and altered cognition via novel object and placement tests. Peptidergic (CGRP+) and nonpeptidergic (IB4+) nociceptive afferent fiber density and distribution was quantified in the cervical and lumbar dorsal horn.
Results
von Frey testing during early post-natal development revealed that HI rabbits exhibit mechanical allodynia in the forepaws and hindpaws over time compared to sham-rabbits. Responsiveness to thermal stimulation was less consistent, with HI kits exhibiting reduced fore- and hindpaw withdrawal latencies at P1 and P5, but not at later times. At P5, peptidergic but not non-peptidergic nociceptive primary afferent fibers expand their topographic distribution in the cervical and lumbar dorsal horn. Preliminary results in P18 spinal cord showed increased distribution of non-peptidergic and not peptidergic afferents. Analysis of nociceptive afferent plasticity at other timepoints is underway. Later in postnatal development, HI kits spend less time in the center of the arena indicative of anxiety-like behavior and are less interested in novel objects or placement indicating deficits in declarative memory. Importantly, there were no differences in the dataset due to the sex of the kits.
Conclusions
: These data show that in addition to motor deficits, an additional characteristic of prenatal injury is pain-like behavior and the expansion of nociceptors. In addition to emulating motor dysfunction seen in CP, prenatal HI in rabbits also recapitulates several features of pain commonly described by people with CP. The expansion of nociceptive primary afferent fibers in the dorsal horn is consistent with findings from other models of chronic pain and may represent a potential druggable target to reduce hypersensitivity and pain unpleasantness in people with CP.
References
Reedich, et. al., Enhanced nociceptive behavior and expansion of associated primary afferents in a rabbit model of cerebral palsy. J Neurosci Res. 2022 Oct; 100(10): 1951–1966.
Presenting Author
Megan Ryan Detloff
Poster Authors
Megan Detloff
PhD
Drexel University
Lead Author
Grace Giddings
Drexel University
Lead Author
Meredith A. Singer
Drexel University College of Medicine
Lead Author
Patrick McGinnis
Drexel University College of Medicine
Lead Author
Landon T. Genry
University of Rhode Island College of Pharmacy
Lead Author
Emily Reedich
University of Rhode Island College of Pharmacy
Lead Author
Elvia Mena Avila
University of Rhode Island College of Pharmacy
Lead Author
Topics
- Pain in Special Populations: Infants/Children