Divergent role for CRF₁ and CRF₂ receptors in the modulation of visceral pain

Abstract

Both anti- and pro-nociceptive effects of corticotropin-releasing factor (CRF) treatment on visceral pain have been reported. Here, this dual action of CRF was differentiated by selective (in)activation of the CRF1 and CRF2 receptor prior to a visceral pain stimulus. Visceral pain was evaluated out of behavioural and visceromotor (abdominal electromyogram) responses to duodenal distension in the freely moving rat. Intraperitoneal (i.p.) CRF (50 microg kg-1) increased the distension-induced visceromotor and behavioural pain response. The pro-nociceptive effects of CRF on the behavioural response were attenuated by a selective CRF1 (CP-154526; 20 mg kg-1) but not a selective CRF2 [antiSauvagine30 (aSVG30); 100 microg kg-1] antagonist. Selective activation of the CRF2 receptor by stresscopin-related peptide (SRP; i.p. 25 microg kg-1) reduced the distension-induced visceromotor and behavioural response. Intrathecal injection of CRF (2 microg 10 microL-1) or SRP (20 microg 10 microL-1) decreased the distension-induced visceromotor and behavioural response. The antinociceptive effects of intrathecal CRF on the behavioural response were attenuated by aSVG30 (20 microg 10 microL-1) but not with CP-154526 (10 microg 10 microL-1). These findings indicate that the CRF1 receptor is involved in pro-nociception of visceral pain, whereas the CRF2 receptor is mainly involved in antinociception. This divergent role of the CRF subreceptors may explain the bimodal effects of CRF treatment on visceral nociception.

Importance of CRF Receptor-Mediated Mechanisms of the Bed Nucleus of the Stria Terminalis in the Processing of Anxiety and Pain

“…Using specific CRF 1 and CRF 2 receptor antagonists, we found circumstantial evidence for both converging and opposing receptor functions, dependent on the behavior under investigation. Although our results support previous reports of CRF receptor function on the anxiety-like behavior in the EPM (Sahuque et al, 2006;Sink et al, 2013) and modulation of somatic pain processing (Ji and Neugebauer, 2008), the observed changes in visceral sensitivity contradicted previous studies using peripherally restricted CRF 1 and CRF 2 receptor antagonists (Greenwood- Nijsen et al, 2005). This suggested that the effects of CRF 1 and CRF 2 receptor activation, at least on visceral sensitivity, may differ depending on the localization of the receptors.…”

Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats

“…In addition, by being able to access the central nervous system, it may be speculated that CP-154,526 abolishes both the central and the peripheral components of the pronociceptive CRF 1 pathway, whereas astressin, being restricted to the periphery due to its chemical properties (20,49), only partially blocks the CRF 1 pathway. Alternatively, our results may also indicate that chronic blockade of CRF 1 with CP-154,526 unmasks the analgesic influence of CRF 2 on visceral nociceptive pathways (35,37,40) leading to the development of analgesia, an effect that was not seen with astressin, which blocks both types of receptors.…”

“…One explanation to these different results may be that both central and peripheral CRF 1 participate to the visceral hypersensitivity induced by chronic WAS. As CRF 2 in the periphery participate to the induction of analgesia (35,37,40), the blockade of visceral hypersensitivity by astressin is likely to be mediated by antagonism of peripheral CRF 1 . In addition, by being able to access the central nervous system, it may be speculated that CP-154,526 abolishes both the central and the peripheral components of the pronociceptive CRF 1 pathway, whereas astressin, being restricted to the periphery due to its chemical properties (20,49), only partially blocks the CRF 1 pathway.…”

Inhibition of Inflammatory Pain by CRF at Peripheral, Spinal and Supraspinal Sites: Involvement of Areas Coexpressing CRF Receptors and Opioid Peptides

“…CRF is in agreement with other studies showing that i.t. CRF inhibited the writhing response in mice Takemori, 1990, 1991) as well as the visceromotor response following duodenal distension (Nijsen et al, 2005). However, these studies examined exclusively visceral pain and no study so far investigated the influence of i.t.…”

“…Only two studies suggested antinociceptive effects following intrathecal (i.t.) CRF administration in visceral pain (Song and Takemori, 1991;Nijsen et al, 2005). Several other studies showed no robust results about CRF's modulation of nociception following its central or sytemic application (Lariviere and Melzack, 2000).…”