ABSTRACT

The hypothalamic peptide somatostatin (SRIF), originally discovered because of its ability to inhibit the release of growth hormone from the pituitary (1), is widely distributed in peripheral organs as well as the brain and spinal cord. The immunohistochemical localization of SRIF in sensory afferent axons terminating in the substantial gelatinosa of the dorsal horn of the spinal cord (2,3), spinal interneurons (4), as well as important pain-regulating centers in the brain, such as periaqueductal gray (5), cingulate cortex (6), and spinal trigeminal nucleus (7), have implicated this neuropeptide as an endogenous regulator of pain transmission. Because SRIF may also be released from the peripheral terminals of capsaicin-sensitive primary afferent neurons (8), sensory neuromodulation may occur at peripheral as well as central loci. The analgesic effect of exogenously administered SRIF was first demonstrated in rats following i.c.v. administration (9), and subsequent studies in humans have demonstrated effective pain relief following intravenous infusions in patients with cluster headache (10), as well as following intrathecal or epidural injections of SRIF to patients with postoperative (11) and cancer pain (12). However, as a consequence of its short half-life, the clinical usefulness of SRIF is limited and metabolically more stable analogues have been developed. The cyclic octapeptide analogues of SRIF, octreotide and vapreotide (RC-160), have been used in clinical as well as animal studies and analgesic activity has been demonstrated following either central or peripheral administration (13-15). For vapreotide, the antinociceptive activity in rats involved an indirect central opioidergic mechanism (15). The widespread distribution of SRIF in the gastrointestinal tract and its presence in the peripheral terminals of sensory afferent neurons has also prompted investigations into the effect of octreotide in patients with irritable bowel syndrome (IBS) who have lowered visceral sensory thresholds. In IBS patients, octreotide caused a significant increase in the threshold for visceral pain perception during colonic distension, to values similar to those obtained in healthy subjects, without modifying colonic compliance (16,17). This suggests that octreotide increases visceral sensory thresholds by inhibiting peripheral nociceptors located in the gut wall,

Table 1 Ligand-Binding Profile of SRIF Analogues on CHO-K1 Cell Membranes Expressing Human Recombinant SRIF Receptorsa

sst1 sst2 sst3 sst4 sst5

SRIF 9.17 9.97 9.10 8.90 9.88 SRIF-28 9.13 8.87 9.20 8.62 9.28 Octreotide 6.20 9.37 8.10 5.61 7.68 Vapreotide 6.37 9.77 7.59 6.65 7.97 BIM-23027 5 9.77 7.70 5.47 7.45 L-362855 6.35 9.00 8.20 7.27 9.55 BIM-23056 6.67 6.98 7.30 7.10 7.83 a Values are pIC50 determined from inhibition of specific [125 I]BIM-23027 (sst2) or [125 I]Tyr11-SRIF binding.