The differential role of specific POMC neuronal circuits in mediating the beneficial and detrimental effects of opioids.

Morphine-like drugs (opioids) have been used and abused for centuries, mainly for their pain-relieving and rewarding effects. These drugs still remain important treatments for pain, however, they have multiple undesirable side-effects which greatly limit their clinical usefulness. These include sedation, suppression of breathing and rewarding effects which can lead to addiction.

Morphine-like drugs work by mimicking the action of chemicals made naturally in the body, called endogenous opioids. The best known of these is beta-endorphin and it has an important role in regulating the pain we experience - especially when we are under stress it can be released to suppress pain perception. This natural release of beta-endorphin does not cause the side effects that are seen with opioid drugs like morphine. This may give us a clue as to how to achieve better pain relief that has reduced side effects.

A first step towards this goal is to better understand the function of the brain circuits that release endogenous opioids. This has previously been difficult as beta-endorphin is made in only two small, inaccessible groups of neurons in the brain. However, by using selective genetic engineering techniques we can introduce modified receptors (DREADDs) into the beta-endorphin releasing neurons of genetically engineered mice. This allows us to selectively activate (or inhibit) these neurons by giving an otherwise inactive drug and study the effects on animal behaviour.

We will test whether the beta-endorphin neurons in the brainstem can produce an analgesic effect; assess whether this is of use in models of chronic pain and also whether this more natural way of releasing opioids exerts a pain relieving effect that is associated with fewer side effects (we believe that there may be reduced sedation, reward and addictive potential). We will also determine whether the pain relief from stress, feeding and vagal nerve stimulation are produced by the activation of these brainstem beta-endorphin producing neurons.

Opioids have potent analgesic properties and remain first rank therapies despite significant adverse central side-effects such as addiction risk, sedation and respiratory depression. The opioid drugs bluntly and globally mimic the action of endogenous opioids, of which beta-endorphin is particularly important in the modulation of pain. The endogenous release of beta-endorphin is not associated with the same profile of side effects but it is not known why. Therefore, a better understanding of the opioidergic circuitry within the brain is needed to help to separate the beneficial from the harmful effects of opioidergic activation.

Beta-endorphin is a cleavage product of pro-opiomelanocortin (POMC) and the primary source in the CNS are the POMC neurons of the arcuate nucleus (ARC) and the nucleus of the solitary tract (NTS). We have recently shown that these NTS neurons produce opioid receptor mediated analgesia and alter cardiorespiratory regulation. Our pilot data indicates that activation of these neurons is anxiolytic but not rewarding or sedating. We propose that activation of the POMC NTS neurons may produce useful analgesia that has fewer confounding side effects.

We will investigate the consequences POMC neuron activation or inhibition using DREADD expression. Excitatory and inhibitory DREADDs will be expressed in ARC or NTS POMC neurons by microinjection of a Cre-inducible viral vector into POMC-Cre mice. These neurons can then be specifically activated or inhibited by administration of CNO.

The role of these neurons will be assessed in several behavioural paradigms i.e. measures of acute pain, anxiety, sedation, reward, and stress-induced analgesia. Furthermore, the analgesic effect of POMC-neuronal activation in the context of chronic neuropathic and inflammatory pain will also be investigated. These studies will increase our knowledge of the endogenous opioid circuits with the goal of identifying novel therapeutic strategies for analgesia.

The research will be of benefit to:
(i) Patients, their families and the wider public
(ii) The medical community
(iii) Pharmaceutical industry
(iv) The research staff employed on the grant
(v) Academia
(vi) Education communities
How will they benefit from this research?
(i) Currently available treatments are ineffective for the majority of chronic pain patients. In large part this is because the underlying neurobiology is unknown. There is an increasing awareness that patients' own endogenous analgesic systems contribute to "pain resilience". By better understanding the workings of the endogenous analgesic circuits we may be able to boost their function and enhance resilience to prevent or recover from chronic pain.
(ii) Treatment strategies for chronic pain patients are misaligned between front-line doctors (e.g. GP) and pain specialists, and largely based on pharmacological interventions that are often ineffective and sometimes counter-productive. As a result, the cost to the NHS is huge and the patient's general health often deteriorates (e.g. opioid dependence). Through effective dissemination of findings within the medical community our research will help to (i) align treatment strategies with the increasing appreciation for the role of central pain control circuits in the development of chronic pain and (ii) strengthen the scientific underpinnings for alternative treatment strategies such as exercise, or psychology to boost resilience therapy; and potentially reveal means to augment their effects.
(iii) Despite urgent need, there have been very few approved drugs with novel targets in the last 10 years for the treatment of chronic pain. The treatments are only effective in around a third of chronic pain patients and opioids remain widely used despite serious known issues with addiction and risk of overdose. Our research will directly benefit the pharmaceutical industry by (i) characterising critical brain circuitry and endogenous opioid function that may lead to the identification of more efficacious therapeutic targets.
(iv) The named researcher will develop novel and state-of-the-art research techniques. There is worldwide shortage of researchers with experimental animal in vivo research expertise. Additionally, the researcher is at a key point in her career and the project will allow her to remain research active in a field that cannot afford to lose skilled investigators. These transferable skills will also be shared with more junior researchers (and undergraduates) in our group and school ensuring that they are retained.
(v) International academia in the fields of pain, psychiatry and addiction medicine, as well as basic scientists in fields of sensory, cardiorespiratory and behavioural neuroscience, are likely to benefit from the progress made by this research.
(vi) Other beneficiaries include those in the field of educational science, the lay public with an interest in neuroscience and school pupils. We will continue to communicate our research findings to a wider audience through public engagement activities outlined in the Pathways to Impact, so that the general public can gain greater insight into neuroscience. This project will also help raise awareness of the potential benefits of animal experimentation and enable non specialists to make informed opinions about this important issue of general interest.