Tonic Control of Peripheral Cutaneous Nociceptors by Somatostatin Receptors

Abstract

The peptide somatostatin [somatotropin release-inhibiting factor (SRIF)] is widely distributed in the body and exerts a variety of hormonal and neural actions. Several lines of evidence indicate that SRIF is important in nociceptive processing: (1) it is localized in a subset of small-diameter dorsal root ganglion cells; (2) activation of SRIF receptors results in inhibition of both nociceptive behaviors in animals and acute and chronic pain in humans; (3) SRIF inhibits dorsal horn neuronal activity; and (4) SRIF reduces responses of joint mechanoreceptors to noxious rotation of the knee joint. The goal of the present study is to show that cutaneous nociceptors are under the tonic inhibitory control of SRIF. This is accomplished using behavioral and electrophysiological paradigms. In a dose-dependent manner, intraplantar injection of the SRIF receptor antagonist cyclosomatostatin (c-SOM) results in nociceptive behaviors in normal animals and enhancement of nociceptive behaviors in formalin-injected animals, and these actions can be blocked when c-SOM is coapplied with three different SRIF agonists. Furthermore, intraplantar injection of SRIF antiserum also results in nociceptive behaviors. Electrophysiological recordings using an in vitro glabrous skin-nerve preparation show increased nociceptor activity in response to c-SOM, and this increase is blocked by the same three SRIF agonists. Parallel behavioral and electrophysiological studies using the opioid antagonist naloxone demonstrate that endogenous opioids do not maintain a tonic inhibitory control over peripheral nociceptors, nor does opioid receptor antagonism influence peripheral SRIF effects on nociceptors. These findings demonstrate that SRIF receptors maintain a tonic inhibitory control over peripheral nociceptors, and this may contribute to mechanisms that control the excitability of these terminals.

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

“…Previous studies have shown that activation of peripheral somatostatin receptors inhibits inflammatory pain and reduces the activity of sensitized nociceptors (6,(8)(9)(10)(11)(12)(13)(14). Local application of SRIF-14 into the inflamed knee joint in rabbits was shown to prevent joint swelling and edema (34)(35)(36).…”

“…Thus, SRIF-14 exerts immunomodulatory effects, such as inhibition of the release of proinflammatory mediators (e.g., interferon-␥ [IFN␥] and tumor necrosis factor ␣ [TNF␣]) (3)(4)(5)(6)(7). In addition, SRIF-14 reduces nociceptive responses (hyperalgesia and pain) in animals and humans by acting on peripheral and central neurons (6,(8)(9)(10)(11)(12)(13)(14). Due to its antiinflammatory as well as antinociceptive effects, somatostatin is an attractive candidate for therapeutic use in immune-mediated painful diseases such as rheumatoid arthritis (RA).…”

Effects of Somatostatin on the Responses of Rostrally Projecting Spinal Dorsal Horn Neurons to Noxious Stimuli in Cats

“…It acts as a neuromodulator that inhibits neuronal activity or modulates neurotransmitter release (Beitz et al, 1983;Patel, 1999). This peptide exists in organs processing nociceptive information, such as small dorsal root ganglion (DRG) cells (Rang et al, 1994;Helyes et al, 2000;Carlton et al, 2001), substantia gelatinosa neurons of the spinal dorsal horn (Hunt et al, 1981), intrinsic interneurones or relay neurons of the superficial dorsal horn (Lu and Ho, 1992;Mather and Ho, 1992), and midbrain periaqueductal gray that projects to the medullary nucleus raphe magnus (Beitz et al, 1983;Millhorn et al, 1987). However, the physiological function of SOM in the spinal nociceptive processing has not yet been fully elucidated.…”

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

“…Small filaments from either the medial or the lateral plantar nerve were repeatedly split with sharpened forceps until single unit activity was obtained by recording with gold wire electrodes. This preparation has been used successfully to record from peripheral primary afferents in our laboratory (Carlton et al, 2001a;Du et al, 2003;Carlton et al, 2004;Du et al, 2006) and others (Lang et al, 1990;Koltzenburg et al, 1992;Rueff and Mendell, 1996).Neurophysiological Recordings-Neural activity was recorded using a DAM80 Differential Amplifier (World Precision Instruments, New Haven, CT). Action potentials were acquired and later analyzed with the CED 1401 (Cambridge, UK) using Spike 2 (v5.08) software.…”