Our group is interested in mechanisms of pathological (clinical) pain and its inhibition by opioids outside the central nervous system (CNS). This can be achieved by activation of opioid receptors on peripheral sensory neurons within injured tissue by exogenous or endogenous opioids. The latter (endorphin, enkephalin) are produced by immune cells infiltrating inflamed tissue. Activation of such cells by stressful stimuli or releasing agents (corticotropin-releasing factor, catecholamines, cytokines, chemokines, bacterial components) releases the opioids and ameliorates pain.

It is important to understand and exploit these mechanisms since there is an urgent need for new medications. This is because of the detrimental side effects of currently available drugs, such as gastrointestinal ulcers, bleeding and heart attacks caused by nonsteroidal analgesics (COX inhibitors), or nausea, constipation, respiratory depression and addiction produced by morphine-like drugs acting on opioid receptors in the CNS. In addition, clinical pain is almost always associated with inflammation, as in surgery, arthritis, invading cancer, inflammatory bowel disease or neuropathic pain (caused by e.g. limb amputation or diabetes).

Inflammation leads to accumulation of opioid-producing immune cells as well as upregulation, enhanced axonal transport and increased G-protein coupling of opioid receptors on peripheral sensory neurons. Thus, these mechanisms offer a promising strategy for the development of new analgesic medications without the hitherto encountered adverse effects. We use molecular, histological, biochemical, electrophysiological and behavioral methods combined with nanochemistry, mathematical modeling and clinical studies in patients.

Pain Schema

From Stein C and Lang LJ. Curr Opin Pharmacol 2009,9(1):3-8.

Opioid peptide-containing circulating leukocytes extravasate upon activation of adhesion molecules (e.g. ICAM-1; beta2 integrin). Corticotropin-releasing factor (CRF), chemokines or noradrenaline (NA, released from sympathetic neurons) can elicit opioid release by activating their respective receptors (CRF receptors, CRFR; adrenergic receptors, AR) on leukocytes. Exogenous opioids (EO) or endogenous opioid peptides (OP, green triangles) bind to opioid receptors (OR) that are synthesized in dorsal root ganglia and transported along intraaxonal microtubules to peripheral (and central) terminals of sensory neurons. The subsequent inhibition of excitatory ion channels (e.g. TRPV1, Ca2+) and of substance P (sP) release results in pain inhibition.