The pain of integrins

Although chronic pain is a common problem, progress in treating it has been relatively slow. Advances in our understanding of neuropathic and inflammatory pain are important if new therapeutic targets are to be identified. In the European Journal of Neuroscience, Dina and colleagues describe a potential role for integrins in mediating this kind of pain.

Integrins are adhesion molecules that are expressed on primary afferent neurons. They bind to elements of the extracellular matrix (ECM) and interact with signalling systems that are known to mediate hyperalgesia. Inflammation and nerve injury cause changes in the ECM around peripheral nerves that might provide important signals to integrins. So, the authors investigated whether integrins were involved in the sensitization of nociceptors that leads to hyperalgesia in animal models of inflammatory and neuropathic pain.

Dina et al. used several methods to interfere with normal integrin signalling in rats, and found that by doing so they could block the development of hyperalgesia. However, there seems to be more than one pathway through which integrins can influence pain.

Fragments of laminin, or antibodies against the integrin subunits that are involved in binding to laminin, blocked hyperalgesia induced by injection of prostaglandin E₂ (PGE₂), but not that induced by injection of adrenaline (epinephrine). The laminin peptides also blocked the induction of hyperalgesia in a slower-acting model of inflammatory pain, the injection of carrageenan. On the other hand, fragments of fibronectin, or antibodies against the subunits of integrin that are needed for bindng fibronectin, prevented the induction of hyperalgesia by adrenaline, but not by PGE₂ or by carrageenan.

The β₁ integrin subunit is involved in the binding of both laminin and fibronectin. When rats were treated with antibodies against this subunit, neither adrenaline nor PGE₂ induced hyperalgesia. The same effect was obtained by treatment with antisense oligodeoxynucleotides that knocked down the expression of the β₁ subunit. The knockdown also prevented hyperalgesia in a model of neuropathic pain caused by the chemotherapeutic drug taxol, and could reverse hyperalgesia if given after taxol treatment.

This evidence that specific integrin subunits are involved in pathways that cause pain when stimulated by different substances should add to our growing understanding of the mechanisms of chronic pain. It might also lead to the development of new therapies for the many patients who are affected by inflammatory or neuropathic pain.