1. Introduction.
Pain is suffered by 30% of adults in developed countries (Sá et al., 2019). The therapeutical plan of chronic pain has traditionally been focused on alleviating the symptomatology. In fact, psychological comorbidities have been overlooked and, in the vast majority, no treatment has been applied. During the last years, pain management has become a multidisciplinary area including different specialist. By applying different psychological therapies in combination with pharmacotherapy and other pain-relief techniques, patients have improve their quality of life, easing their pain sensation, diminishing the possibility of disability, and reducing fear-avoidance behaviours (Petrucci et al., 2022). Interestingly, men and women show different pain physiopathology resulting in discrepancies in pain feeling, response to pain killers and psychological comorbidities (Edwards et al., 2003; Pieh et al., 2012; Popescu et al., 2010; Riley et al., 1998). Nevertheless, since females have traditionally been excluded in research (Burek et al., 2022), the lack of sex-based studies could have led to undertreat pain-related conditions in women, promoting chronic pain and the development of neuropsychiatric comorbidities (Cáceda et al., 2021; Jakubczyk et al., 2016). Moreover, a metanalysis performed by Burek and collaborators showed that the classical behavioural tests of anxiety- and depression-like behaviours in the presence of pain lead to contradictory results depending on the strain, source, sex of the animal and testing time after the induction of pain (Burek et al., 2022)
Recent reports highlighted that pain induces alterations in the mesocorticolimbic system (MCLS) in both, kappa opioid receptor (KOR)/dynorphin (DYN) and corticortropin-releasing factor (CRF) systems (Fu & Neugebauer, 2008; Ji et al., 2007; Markovic et al., 2021; Massaly et al., 2019; Mazzitelli et al., 2022; Navratilova et al., 2019). Along with other effects within the MCLS, the KOR/DYN system recruitment in the nucleus accumbens (NAc) has shown to mediate negative affective states induced by inflammatory and neuropathic pain (Liu et al., 2019; Massaly et al., 2019). Additionally, presence of inflammatory pain has led to alterations in the CRF 1 receptors (CRF1R) transmission in central amygdala (CeA) (Fu & Neugebauer, 2008; Ji et al., 2007). In fact, CRF1R activation in CeA is necessary to develop pain-related anxiety-like behaviour, and the activation of KORs in CeA disinhibits CRF1R producing pain-related anxiety-like behaviour (Hein et al., 2021; Ji et al., 2007; Mazzitelli et al., 2022). Furthermore, the optoinhibition of CRF containing neurons in CeA is sufficient to impair anxiety-like behaviour induced by pain (Hein et al., 2021; Mazzitelli et al., 2022). Interestingly, KOR blockade in CeA controls pain-related behaviour in a model of functional pain by restoring synaptic inhibition of CeA-CRF neurons, demonstrating that KOR and CRF systems are closely related in pain and its comorbidities (Yakhnitsa et al., 2022). However, most of these cited papers have obtained these results only in male rodents leaving females understudied.
In order to shed light on the time course and sex-dependent effects of pain-induced comorbidities, here we will use male and female rats to be tested in classical anxiety/depression behavioural assays for a total period of three weeks. Additionally, we will study the CRF and KOR/DYN systems alterations in the MCLS that may be implicated in the observed behaviours.