title: Neurobiological mechanisms underpinning altered pain processing in a preclinical model of autism
Creators: name: Humphrey, Rachel M.
Publisher: name: University of Galway
Year: 2024
Subjects: subject: Pain
subject: Autism
subject: Valproic Acid
subject: animal model
subject: sex differences
subject: nociception
subject: Medicine
subject: Physiology
subject: FOS: Biological sciences

description: Autism is a neurodevelopmental condition which affects 1 in 36 children. Up to 90% of autistic individuals experience some form of sensory dysfunction, including alterations in somatosensory and pain responding. Autism is also associated with an increased incidence of chronic pain, with autistic females identified as being at greater risk. The behavioural alterations associated with autism, such as impaired communication, altered sensory perception, and self-injurious behaviour, dramatically complicates pain assessment and management. Consequently, although altered pain sensitivity and communication in autism are well recognised, sex differences in pain in autism and the underlying neurobiology are poorly understood. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of autism. Rodents prenatally exposed to VPA exhibit an autistic-like behavioural and neurobiological phenotype, similar to that observed clinically, including a few studies demonstrating altered pain behaviour. The endogenous cannabinoid and opioid systems have been shown to play a role in both the pathophysiology of autism and pain processing. Thus, it was hypothesised that alterations in these neuromodulatory systems, in key spinal and supraspinal regions involved in pain signalling, may underpin the altered pain-related behaviour evident in the VPA model. The data presented in this thesis add to this knowledge and demonstrate for the first time that prenatal VPA exposure results in hyposensitivity to acute noxious mechanical and heat stimulation, and a sex-dependent transient hyposensitivity to acute inflammatory pain (Chapter 3). These behavioural changes were associated with sexually dimorphic alterations in the expression of the immediate early gene c-fos in the prefrontal cortex and endocannabinoid and opioid system-related gene expression in the lumbar spinal cord of VPA-exposed rats. Thus, the data in Chapter 3 suggests that changes in the endocannabinoid and opioid system may be associated with altered acute pain-related behaviour in the VPA model. Chapters 4 and 5 explored, for the first time, the effect of a chronic inflammatory pain stimulus on sensory and affective responding in adolescent male and female rats and examined if this was altered by prenatal VPA exposure. The data demonstrate that prenatal VPA exposure sex-dependently reduces the magnitude and shortens the time course development of mechanical and thermal hypersensitivity and pain-related negative affective behaviour in the complete Freund’s adjuvant model of chronic inflammatory pain. VPA-exposed male, but not female, rats exhibit reduced chronic pain-related negative affective behaviour, effects which were associated with reduced c-fos expression and alterations in opioid system-related gene expression in the anterior cingulate cortex (ACC). VPA-exposed female rats also exhibited decreased affective-motivational chronic pain-related behaviour, effects which were not associated with changes in neuronal activation in the ACC. In conclusion, the novel data presented in this thesis adds to the body of knowledge and highlights the complex interplay between prenatal VPA exposure, sex, and pain, emphasising the importance of considering sex-specific mechanisms in understanding and managing pain in autistic individuals.