Standardization and new development of pain-related models and methods in rodents and humans

Folie1Background and central theme

Ensuring homogeneity of model systems and analytical methods is critical for facilitating comparison and association of structure-function paradigms across projects and drawing mechanistic commonalities across different pain disorders. Moreover, there is an urgent demand for developing new model systems as well as methods for promoting forward and reverse translation between rodent analyses and human studies in the context of understanding and treating pain. These constitute the two main central themes of S01.

Rodent studies:

Many of the projects within this consortium utilise experimental rodent models, mimicking human diseases conditions, to study a broad range of diverse pain-related questions. Therefore, project S01 will endeavour to address four principal current deficits in the field in order to promote translation between humans and rodents:

First, some chronic pain disorders which are clinically prominent in this proposed consortium have not been adequately modelled in rodents.

Second, even widely-used, established models as well as behavioural tests can take a highly variable and inconsistent course across laboratories, rendering comparative and mechanistic analyses difficult.

Third, spontaneous pain and affective pain states are often underrepresented in behavioural analyses on rodents, which represent a very timely and much debated topic in pain research.

Finally, the impact of anxiety and depression on pain has not been adequately modelled in rodents.

Human studies:

While stimulus-evoked responses are standard tools to assess excitability changes in animal models of acute and chronic pain, human patients complain of ongoing pain and comorbidities such as sleep disturbance, depression and anxiety, thereby rendering a gap between analytical paradigms employed in animals and humans. Although studies in rodent models indicate functional and structural plasticity in pain-related circuits in chronic pain states, whether these changes really match human chronic pain states is unclear and not yet adequately addressed. This translational gap, which is a major obstacle to progress in pain therapy, should not only be closed from the preclinical side but also from the clinical side. For this purpose it is necessary to refine and standardize methods for the quantification of plasticity in pain-related circuits in humans and apply them to a range of pain disorders. Central sensitisation and descending facilitation have been studied extensively across many rodent models of acute and chronic pain [19,20]. The human part of S01 will therefore focus on spinal signal processing in humans and its modulation by descending controls.

First, we will assess mechanisms of central sensitisation and the influence of descending controls in patients with various types of pain disorders.

Second, we will provide support to clinical departments on assessment of nociceptive pathways in humans.

Finally, we will assess the effects of fear on central sensitisationFolie2

Key Questions for the first funding period:

Rodent studies:

  1. Develop mouse models for chronic back pain and phantom limb pain.
  2. Establish standard operating procedures (SOPs) for all rodent models and behavioural tests and help to implement these uniformly and consistently across all projects.
  3. Optimise and develop measurements for spontaneous pain and the affective component of pain in rodents.
  4. Study impact of anxiety and depression on pain in rodents

Human studies:

  1. Assess differences in spinal excitability and descending pathway sensitivity across a selected cross-section of chronic pain patients studied in the consortium (diabetes, spinal cord injury, low-back pain, phantom limb pain)
  2. Relate differences in clinical phenotypes of patients to differences in central sensitisation
  3. Study impact of fear and stress on spinal excitability and descending pathway sensitivity in humans. 

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