A role for peripheral somatostatin receptors in counter-irritation-induced analgesia

Our hypothesis is that peripheral somatostatin (SRIF) has a role in counter-irritation-induced analgesia. Our paradigm involves the reduction of nociceptive behaviors produced by primary noxious stimuli (formalin or complete Freund's adjuvant [CFA] in the rat hind paw) by a counter-irritating stimulus (capsaicin [CAP] in the tail or muzzle). Activation of peripheral SRIF receptors is key since an SRIF receptor antagonist cyclo-somatostatin (c-SOM) and SRIF antibodies in the hind paw attenuate the counter-irritation-induced analgesia of both formalin and more persistent CFA nociception. Specificity of c-SOM is shown by reversal of its effects with octreotide, a SRIF analog. Injection of formalin in one hind paw and c-SOM in the other does not reduce the counter-irritation analgesia demonstrating local action of the c-SOM. Approximately 33% of peripheral sensory axons contain SRIF, which could release the peptide to activate SRIF receptors on cutaneous axons. Intraplantar naloxone has no effect on the counter-irritation analgesia indicating that SRIF is not activating opioid receptors. These results indicate that in addition to the classic central descending noxious inhibitory control systems that underlie counter-irritation-induced analgesia, there is a peripheral contribution arising from activation of SRIF receptors. Identifying a peripheral contribution of SRIF to mechanisms of counter-irritation analgesia offers opportunities for peripheral therapy.