Dr John Harris
Lecturer in Neurophysiology
John's research investigates mechanisms behind acute and chronic pain by measuring spinal reflexes using electrophysiological recording and motion analysis techniques. Current research includes:
- How individual muscles in a limb are organized in producing a withdrawal reflex
- How this organization changes in acute and chronic pain states
- The mechanisms underlying excitability changes in the spinal cord ('central sensitization') in pain
- Pain in rheumatoid and osteoarthritis and development of more effective analgesics
- The treatment of osteoarthritis in dogs
I am the module convenor and primary contributor on neurophysiology modules taught as part of BSc degrees offered within the School of Biosciences. In addition I lecture and run practical classes on… read more
Withdrawal reflexes are the simplest centrally-organized responses to painful stimuli hence they are often used for the study of nociception, however few studies examine the withdrawal response in… read more
I am the module convenor and primary contributor on neurophysiology modules taught as part of BSc degrees offered within the School of Biosciences. In addition I lecture and run practical classes on various other modules within the School of Biosciences.
Level 1: D212Z5 - Introductory Physiology
Level 1: D21BP1 - Bioscience Tutorials (Academic Development)
Level 2: D223A8 - Physiology of Electrically Excitable Tissues (Module convenor)
Level 3: D236Z4 - Systems Neurophysiology (Module convenor)
Level 3: D23PRO - Undergraduate Research project (5 - 7 students per year)
Nominated for Lord Dearing Award in 2012
Awarded Physiological Society poster prize in 2012 (Education & Teaching theme) for presentation "On-line discussion groups as a tool for enhancing student understanding following practical-based teaching". Proc. Physiol. Soc., 27: PC276.
Animal Sciences staff representative on the Learning Community Forum (formerly the Undergraduate Student-Staff Feedback Committee)
Withdrawal reflexes are the simplest centrally-organized responses to painful stimuli hence they are often used for the study of nociception, however few studies examine the withdrawal response in any detail. The organization of limb withdrawal was first described by Charles Sherrington at the start of the 20th century, who proposed that withdrawal to a transient stimulus was a stereotypical response involving excitation of all flexor muscles in a limb with concomitant inhibition of extensor muscles: the 'flexor reflex'. However recent studies on the organization of withdrawal reflexes suggest they produce the most appropriate movement depending on the site of the stimulus and that each hind limb muscle has an excitatory receptive field overlying the area withdrawn by contraction of that muscle. The total movement generated by a noxious stimulus is therefore the result of collective activation of reflexes to those muscles that have excitatory receptive fields overlapping the point of stimulation. This 'modular theory', first proposed by Jens Schouenborg, means extensors as well as flexors can act as the primary movers. Studies in the Harris laboratory have recently focused on how reflex responses are (re-)organized following injurious peripheral stimuli. Injurious stimuli augment the protective function of reflexes by enhancing (sensitizing) reflexes that protect the injured site and inhibiting those reflexes that might exacerbate the site of injury. The group has shown that the areas from which a reflex can be sensitized closely match those from which the reflex itself can be evoked, provided the spinal cord is intact. If descending pathways are interrupted, sensitization can be evoked from a much wider area. Thus whether the reflex is sensitized or inhibited after an injury depends on the relationship between the site of the injury and its relationship to the movement made by the reflex. The nature of the pathways that control these 'sensitization fields' is also of great interest to the group. Major projections from the brain to the spinal cord contain the neurotransmitters noradrenaline or 5-hydroxytryptamine (5-HT, serotonin) hence these pathways are prime candidates to study pharmacologically in order to tap into endogenous systems towards the possible benefit of pain relief.
Most recently, in collaboration with other groups at Nottingham (Dr Sara Kelly), the research has been particularly targeted towards the potential sensitization and reorganization of reflex responses in arthritic pain states and the influence of descending pathways. Osteoarthritis (OA) is a degenerative joint disease affecting almost 40% of the population aged over 60 as well as being a major debilitating disease in animals, leading to chronic pain and disability. Understanding the mechanisms that drive and maintain OA pain is therefore critical for the rational development of effective therapies. In line with our previous research, evidence suggests that plasticity within the central nervous system ('central sensitization') contributes to the maintenance of OA pain. In further collaboration with Dr Jo Murrell (Bristol University) we hope to translate the groups findings over to a clinical setting by studying reflex responses in dogs with arthritis, in the hope of developing better diagnostic capability and a more targeted treatment regime.
Measurement of limb movements during reflex withdrawal
All previous work on the organisation and re-organisation of withdrawal reflexes had been based on the measurement of electrical signals rather than the actual movements made. Thus, the primary objective of these studies was to quantify the movements generated in withdrawal reflexes, by measuring 3-dimensional position changes (Codamotion®) of a limb evoked by mechanical stimulation of selected parts of the same limb. Once the "normal" organisation of reflex movements was mapped, we examined how reflexes were altered by (i) acute noxious stimulation of strategically-selected parts of the foot; (ii) analgesic drugs, (iii) disruption of endogenous control systems; and (iv) acute and chronic inflammation. This was the first time that the stimulus site-dependence of the movements generated in response to cutaneous stimulation had been studied.
Pharmacology of 'central sensitization'
We have also investigated some of the neurotransmitters behind (central) sensitization of reflex responses. In agreement with others, we have confirmed the importance of the NMDA subtype of glutamate receptor in central sensitization however we found no evidence for a role of Group I metabotropic glutamate receptors in this process. Simultaneous blockade of all tachykinin receptors was required to reveal their role in central sensitization of reflexes. Simultaneous block of tachykinin and GluN2B-subunit containing NMDA receptors indicated that a combined pharmacological approach offers a potential way forward for the development of new anti-hyperalgesic agents.
Opioids as analgesics
Opioids are important analgesics in animals and man but their effectiveness can be radically altered in some chronic pain states. Against inflammatory pain they are generally found to be more potent compared to use in acute pain, however for the treatment of pain following nerve injury (neuropathic pain), opioids can be completely ineffective. Research into the mode of action of opioids is therefore of major importance. A crucial site at which the inhibitory effect of opioids is mediated is the spinal cord (as evidenced by their effectiveness following epidural application), however opioids also have an action in the brain, where it is thought they cause disinhibition (i.e. an overall facilitation) of inhibitory pathways to the spinal cord thereby suppressing the transmission of nociceptive information. Thus one possible explaination for the reduction in efficacy of opioids in neuropathic states is the breakdown of opioid-activated descending inhibition to the spinal cord. Our previous studies therefore looked further at the involvement of these pathways from the brain in determining the potency of opioids, and how their interaction might change in inflammatory and neuropathic conditions. Studies such as these aid in the design of analgesic strategies for long-term pain states.