Central CRH administration changes formalin pain responses in male and female rats

Abstract

Corticotropin-releasing hormone (CRH) is suggested to be involved in the regulation of pain. To better evaluate the CRH-mediated behavioral alterations in the formalin inflammatory pain test, we administered CRH or the CRH receptor antagonist α-helical CRH_9–41 (ahCRH) intracerebroventricularly to male and female rats and compared the effects with those of saline control. Nociceptive stimulation was carried out through a subcutaneous injection of dilute formalin (50 μL, 10%) in the plantar surface of the hind paw. In both sexes, formalin-induced responses, recorded for 60 min, were affected by CRH but not by ahCRH treatment. Paw flexing duration was decreased in both sexes during the formalin interphase period in the CRH-treated group compared to saline control groups; however, licking of the injected paw was markedly increased by the same treatment at other time periods. Treatments induced only a few changes in spontaneous non-pain behaviors, which do not account for the effects on pain response. In conclusion, these data demonstrate the ability of CRH to affect the behavioral responses to an inflammatory nociceptive stimulus, and that the effects can be in opposite directions depending on the behavioral response considered.

Introduction

Hypothalamic–pituitary–adrenal (HPA) axis hormones have attracted the attention of many research groups due to their importance in stress. In particular, corticotropin-releasing hormone (CRH), known to trigger and regulate the release of pro-opiomelanocortin-derived peptides from the pituitary gland, also acts in the central nervous system (CNS) as a neurotransmitter and/or neuromodulator and is able to produce a variety of endocrine (Vale et al., 1981, Steckler, 2001), behavioral (De Souza, 1995, Dunn and Berridge, 1990, Smagin et al., 2001, Yarushkina, 2008) and autonomic effects (McNally and Akil, 2002, Chrousos and Gold, 1992). Under stressful conditions, CRH increases sensitivity and reactivity to aversive stimulation (Dunn and Berridge, 1990, Adamec and McKay, 1993, Koob et al., 1993); for instance, CRH administration increases the time spent freezing or shock-induced fighting (Dunn and Berridge, 1990, Koob et al., 1993, Menzaghi et al., 1993). The behavioral effects of CRH can be independent of HPA axis activation (Adamec and McKay, 1993, Menzaghi et al., 1993), showing that CRH can mediate the responses to stressors both via the HPA axis and independently of the HPA axis (De Souza, 1995, Adamec and McKay, 1993).

The role of CRH in pain and analgesia has been neglected until recently (Lariviere and Melzack, 2000). Earlier studies showed that CRH has analgesic or anti-hyperalgesic effects in rodent somatic pain models of thermal and inflammatory pain and in visceral inflammatory pain models of intraperitoneal injection of irritants (Lariviere and Melzack, 2000, Vit et al., 2006). In contrast, CRH consistently has hyperalgesic effects in irritable bowel syndrome models of visceral hypersensitivity (Taché et al., 2005). Only recently has CRH been suggested to have hyperalgesic effects in a prolonged somatic inflammatory model, inferred from the effect of a CRHR1 receptor subtype antagonist in neuropathic pain (Fu and Neugebauer, 2008, Bourbia et al., 2010). It is possible that some of the differences in the above results are due to sex differences of the tested rodents. Indeed, sex differences are present in pain and, in particular, in chronic stress-related painful syndromes, with a higher incidence in females than in males in both humans and experimental animals (Aloisi, 2003, Greenspan et al., 2007, Bourbia et al., 2010)].

The present study examines for the first time the effect of centrally administered CRH in male and female rats subjected to the formalin inflammatory pain test to determine the robustness of previous contradictory findings in inflammatory pain models. Both CRH and CRH receptors are widespread in the CNS. Thus central intracerebroventricular (ICV) injection ensures a wide activation of the CRH system, including specific areas such as the amygdala recently shown to play an important role in CRH-mediated pain modulation (Lariviere and Melzack, 2000, Fu and Neugebauer, 2008, Bourbia et al., 2010). Pain behaviors typically observed in the formalin test were recorded, as were spontaneous non-pain behaviors during the same period.