Nociception and pain in the developing rodent cortex

Pain is essential for survival and even newborn animals display strong behavioural reactions to potential injury. However, it is not known whether the newborn brain is wired up to experience the unpleasantness of pain as well as its unique sensory qualities. This is important for understanding whether young animals suffer from pain in the way that adults do and how we can best relieve that suffering. We have recently developed a method of real time, stress-free, wireless recording from the brain of awake, rat pups while they remain free to move about with their littermates and mother. We will use this method to investigate the emergence of pain-related activity in the developing brain, and its sensitivity to pain-relieving treatment.
In adults, we know that the brain can reduce or enhance pain experience, as when attention is diverted or expectation increased, but again we do not know if this occurs in young animals. We will discover at what age this 'top down' control of pain develops, using new wireless light based stimulation techniques to control selected brain regions at different ages. This will tell us at what age animals are able to control their own pain.
Inevitably, some young animals do get injured, either accidently or due to required clinical or agricultural procedures. We will investigate whether such early life injury leaves a 'memory trace' in the brain, by altering the future growth of some brain regions or by changing normal pain related brain activity in later life.
The results of this research proposal will provide a scientific basis for better pain measurement and prevention in young animals.

The aim of this proposal is to discover how pain processing emerges in the developing rodent cortex. While it is clear that newborn rodents react to noxious stimulation, little is known about the postnatal development of the higher level brain networks required for the perception and affective processing of pain. We will use real time, stress-free, telemetric ECoG (electrocorticographic) recording from awake, freely moving rat pups of different ages to investigate the emergence of dynamic pain activity in the two key cortical areas associated with pain (i) the somatosensory cortex (S1), associated with sensory qualities, such as intensity and location and (ii) the medial prefrontal cortex (mPFC), associated with the emotional qualities of pain. We will use graded mechanical and thermal cutaneous hindpaw stimulation in awake pups to measure 'nociceptive' cortical activity and mild tissue injury and hyperalgesia models to characterise the developmental pattern of cortical network activity associated with 'tonic' pain. In separate experiments, we will establish a link between the maturation of ascending cortical activity with that of descending, top down cortical control of pain behaviour using telemetric optogenetic techniques to selectively manipulate neuronal activity in the two cortical regions, at different stages of postnatal development. Finally, we will investigate the effect of early life tissue injury upon the postnatal development of cortical pain networks using established models of neonatal injury, such as unilateral plantar incision, followed by whole-brain high-resolution structural MRI to quantify cortical growth and telemetric ECoG recording of cortical pain activity. This proposal will fill a large gap in our knowledge of the development and plasticity of cortical pain processing and pain control.

Who might benefit from this research?
- Veterinary and Human Clinical health care professionals concerned with the management of pain in young animals and children
- Biological Services and other professionals concerned with laboratory animal welfare and the NC3Rs
- Pharmaceutical Industries concerned with the development of new analgesics for young patients
- Charities and Public Interest concerned with better information about pain in young animals and children

How might they benefit from this research?
- Veterinary and Human Clinical health care professionals: Knowledge of how the brain processes pain in young animals will shape future pain management
- Biological Services and NC3Rs professionals: Our approach of wireless recording and stimulation while keeping young rats in their litters will influence future guidelines for developmental research.
- Pharmaceutical Industries: Knowledge of the sensitivity of the young brain to analgesic agents will inform the search for and development of new targets.
- Charities and Public Interest concerned with better information about pain in young animals and children: Results from the current proposal will inform the public about pain in young animals and children and direct future research.