AbstractsBiology & Animal Science

Priming of inflammatory pain responses by a neonatal immune challenge: implications of neuroimmune-endocrine communication for pain

by Ihssane Zouikr

Institution: University of Newcastle
Degree: PhD
Year: 2014
Keywords: programming of pain; neuroimmune interface in pain; thesis by publication
Record ID: 1051853
Full text PDF: http://hdl.handle.net/1959.13/1055978


Research Doctorate - Doctor of Philosophy (PhD) The perinatal period, which encompasses both in utero and neonatal life, represents a time of significant plasticity during which many physiological systems including the immune, endocrine, and nociceptive systems are undergoing fine-tuning and maturation. Thus, an exposure to environmental stimuli during this sensitive period of development can interfere with the normal developmental trajectory of these physiological systems, leading to maladaptive responses later in life. Several animal and human studies have documented that exposure to a variety of stressors such as psychological, physiological, or social stress, can critically influence how organisms evolve and respond to their environment later in life. One factor that has recently received considerable interest is exposure to bacteria during the neonatal period. Exposure to the bacterial mimetic, Lipopolysaccharide (LPS), is an established model of early life immune-mediated stress. Our laboratory has previously shown that neonatal LPS exposure is associated with altered behavioural, endocrine, and immune responses later in life. However, the impact of neonatal LPS exposure on nociceptive responses later in life is less known. The primary aim of the current thesis was to develop a profile of the formalin-induced behavioural alterations that are associated with neonatal LPS exposure, as well as characterizing the neuroendocrine, neuroimmune, spinal, and supraspinal changes associated with this behavioural profile. To achieve this aim, we have subjected Wistar rats to intraperitoneal administration of LPS (LPS, Salmonella enterica, serotype enteritidis) on postnatal days (PNDs) 3 and 5 (birth = PND 1) and subjected them to formalin injection at PNDs 7, 13, 22, and 80-97. The first manuscript (Zouikr et al., 2013) examined the impact of low formalin concentrations, not previously used in the literature, on formalin-induced nociceptive responses (i.e. flinching and licking) during the first three postnatal weeks in rats. The results indicated that low formalin concentrations (0.3-2.25%) induced developmentally regulated pain responses. The characteristic biphasic nociceptive response appeared as early as PND 13 following an intraplantar injection of 0.8% formalin. Additionally, we demonstrated that PNDs 7, 13, 22 and adult rats displayed fine-tuned responses with low formalin concentrations including appearance of licking responses in one week old rats. Following the optimization of the formalin test, in the second manuscript (Zouikr et al., 2014b), we investigated the behavioural profile of infant and preadolescent rats following exposure to an immune challenge during the neonatal period. We demonstrated for the first time that dual exposure to LPS at PNDs 3 and 5 exerts long-term effects on inflammatory pain responses in a developmentally regulated manner. An increased susceptibility (i.e. hyperalgesia) to formalin-induced licking (at PND 13) and flinching (at PND 22) responses was observed following neonatal LPS…