Background & Aims
Neonates display altered responses to noxious stimuli compared to adults, with lower behavioural pain thresholds and exaggerated responses to nociceptive stimuli (Andrews et al., 2002; Waldenström et al., 2003). The 4th postnatal week represents a key epoch in the maturation of endogenous pain control pathways in rodents, equivalent to preadolescence in humans. This period is critical in the maturation of descending spinal projections from the rostral ventral medulla. Endogenous opioid peptides are crucial mediators of this maturational process (Hathway et al., 2012). Although surgery at this age is a risk factor for developing chronic pain in later life (Kristensen et al., 2010), the potential impact of opioid analgesia exposure remains unknown.
We aim to advance understanding of the effects of early postnatal morphine exposure on pain and anxiety responses in adulthood.
Methods
Sprague Dawley rat pups (5?, 5?) were treated with morphine (s.c., 3mg/kg, twice daily, n=5) or saline (1mL/kg, n=5) for 7 days from postnatal day (P) 21 until 28. Nociceptive thresholds (via application of von Frey filaments), locomotor activity, and anxiety scores (elevated plus maze) were assessed from P29 to P40. From P42-45, a subset of rats were anaesthetised (n=4) and a laminectomy performed to expose the L4/5 spinal cord for in vivo multi-electrode array (MEA) recordings across all laminae of the dorsal horn (DH). Whole DH responses to a range of mechanical (2-26g) and electrical (0.5-5mA) stimulations of the hindpaw were recorded at baseline, and 30mins after 2 successive systemic cumulative doses of morphine (0.5, 2.5mg/kg, s.c.), followed by a single dose of the mu opioid receptor antagonist naloxone (1mg/kg, s.c.).
Results
A significant increase in nociceptive thresholds was observed with age (F(3,24) = 2.171, p<0.001), corroborating previous literature (Andrews et al., 2002; Waldenström et al., 2003). Morphine exposure in the 4th postnatal week had a sex-specific effect on mechanical nociceptive thresholds in adulthood (P40+). Morphine-exposed males had significantly higher nociceptive thresholds relative to both saline-exposed males (F(1,6) = 11.67, p= 0.0074) and female morphine-exposed rats (p= 0.0102). There was a trend towards sex-specific effects of morphine exposure on locomotion and anxiety-like behaviour. In male rats, postnatal morphine was associated with lower activity and a reduced anxiety-like behaviour, relative to controls. Female morphine-exposed rats showed the opposite phenotype, with greater activity and anxiety compared to saline-treated controls. A replication study will be undertaken. Ongoing MEA recordings are investigating the neuronal basis for these differences in nocicept
Conclusions
Opioids are important clinical tools for the control of post-surgical and other procedural pain across the life course. We have studied the impact of the administration of morphine, the prototypical opioid analgesic, in pre-adolescent rats. Our data indicate that morphine exposure during this critical preadolescent period alters normal maturation of pain and anxiety responses in a sex-dependent manner. Further work is being undertaken to elucidate the mechanisms that underpin this.
References
Andrews, K. A. et al. (2002) ‘Abdominal sensitivity in the first year of life: Comparison of infants with and without prenatally diagnosed unilateral hydronephrosis’, Pain, 100(1–2), pp. 35–46. doi: 10.1016/S0304-3959(02)00288-9.
Hathway, G. J., Vega-Avelaira, D. and Fitzgerald, M. (2012) ‘A critical period in the supraspinal control of pain: Opioid-dependent changes in brainstem rostroventral medulla function in preadolescence’, Pain. International Association for the Study of Pain, 153(4), pp. 775–783. doi: 10.1016/j.pain.2011.11.011.
Kristensen, A. D. et al. (2010) ‘Chronic pain in adults after thoracotomy in childhood or youth’, British Journal of Anaesthesia. British Journal of Anaesthesia. Published by Elsevier Ltd., 104(1), pp. 75–79. doi: 10.1093/bja/aep317.
Waldenström, A. et al. (2003) ‘Developmental learning in a pain-related system: Evidence for a cross-modality mechanism’, Journal of Neuroscience, 23(20), pp. 7719–7725. doi: 10.1523/jneurosci.23-20-07719.2003.
Presenting Author
Neave Smith
Poster Authors
Topics
- Models: Acute Pain