Dual peripheral actions of immune cells in neuropathic pain

Ability to perceive physiological pain is essential in protecting the individual from tissue destruction. In contrast, pathological chronic pain is an expression of maladaptive alterations outlasting its biological usefulness. In such conditions even eating, speaking or wearing clothes might be painful, as in neuropathic pain. Such pain is caused by diseases or injuries affecting nerves (e.g. diabetes, trigeminal neuralgia or amputation). Neuropathic pain is not an exclusive neuronal phenomenon but also involves immune responses. Damaged peripheral nerves are infiltrated by mast cells, granulocytes, macrophages and T lymphocytes. It is widely emphasized that these cells, via secretion of inflammatory mediators (e.g. proinflammatory cytokines, chemokines), contribute to the generation of neuropathic pain. However, leukocytes are also a source of analgesic mediators such as anti-inflammatory cytokines and opioid peptides. Recent findings indicate that immune cell-derived opioid peptides can interact with opioid receptors in the injured nerves and ameliorate neuropathic pain. Targeting opioid-containing immune cells might represent a new disease-modifying approach based on the use of beneficial effects of neuro-inflammation in painful neuropathies. This review analyzes both detrimental and advantageous actions of leukocytes at peripheral nerves in neuropathic pain.