Role of nociceptin/orphanin FQ in thermoregulation
Introduction
In 1994, several laboratories described a G-protein-coupled receptor (GPCR) homologous to the classical opioid receptors. This receptor was classified as an orphan receptor (Meunier et al., 1995). Soon thereafter, two distinct research groups isolated an endogenous heptadecapeptide termed nociceptin or orphanin FQ (N/OFQ) that could bind to this receptor (Meunier et al, 1995, Reinscheid et al, 1995). The name nociceptin was chosen to specify its pronociceptive behavior. The word orphanin FQ indicates its binding activity to the cloned orphan receptor.
N/OFQ displays sequence homology with classical opioid peptides but with a distinct pharmacological profile. Initially, it was considered an opioid-like peptide because it is structurally related to endogenous opioids, particularly dynorphin A; however, it does not bind to opioid receptors (Reinscheid et al., 1995). After the discovery of N/OFQ, the orphan receptor was defined as the N/OFQ receptor (NOP) (also known as opioid receptor like-1 or ORL-1) (Mogil and Pasternak, 2001). The N/OFQ peptide precursor (ppN/OFQ) and NOP receptors are widely expressed in the nervous systems and in peripheral organs, as well as in the immune system.
The occurrence of N/OFQ and the NOP receptor in brain areas has been investigated (reviewed in Mogil and Pasternak, 2001). Those studies showed a similar distribution of the NOP receptor and NOP mRNA. The brain distribution of N/OFQ has also been reported in the literature (Mogil, Pasternak, 2001, Neal et al, 1999), and it corresponds to the distribution of the NOP receptor. N/OFQ and the NOP receptor have been found in the cortex, septum, hippocampus, amygdala, substantia nigra, raphe nuclei, locus coeruleus, and spinal cord. According to Letchworth et al. (2000), the NOP receptor binding densities (expressed as fmol/mg tissue ± standard error of the mean) in rat hypothalamic nuclei were as follows: suprachiasmatic, 10.5 ± 4.3; supraoptic, 6.3 ± 0.7; ventromedial, 6.3 ± 0.9; lateral, 5.9 ± 0.2; preoptic, 5.7 ± 1.3; mammillary, 5.6 ± 0.1; paraventricular, 5.5 ± 0.1; arcuate, 5.2 ± 0.8; periventricular, 4.6 ± 0.3. The highest concentration of NOP binding sites was detected by those authors in the locus coeruleus (16.1 ± 1.1) and motor cortex (12.1 ± 0.5).
The presence of N/OFQ and NOP receptor in the above mentioned areas seems to be indicative of any contribution of this peptidergic system in motor control, reward, pain transmission, the stress response and in the control of autonomic functions, including body temperature (Neal et al., 1999).
Pain transmission at the supraspinal and spinal levels has been deeply investigated. In several studies, N/OFQ has been administered in animal models of pain together with receptor antagonists or antisense compounds, confirming the selective role of this peptide in pain control. Furthermore, transgenic knockout rodents have been developed to ascertain the participation of N/OFQ in different biological phenomena.
NOP receptor signals via the activation of adenylyl cyclase (AC)-inhibitory (Gi/Go) GTP-binding proteins. It has been suggested that the probability of NOP receptor/G protein interaction is enhanced by compartmentalization in the membrane (Connor et al., 1996), allowing the rapidity of GPCR signal propagation (Hur and Kim, 2002).
NOP receptor activation by its natural ligand or synthetic agonists induces the activation of K+ conductance and inhibition of voltage-gated Ca2+ channels and either may augment (via activation of the G α-subunit class of G-protein) or decrease (via the Gi/Go class of G-protein) cAMP formation in various cell models (Baiula et al, 2013, Levitt et al, 2011, Meunier, 1997, Meunier et al, 1995, Neal et al, 1999, Reinscheid et al, 1995).
Spampinato et al. have proven that NOP receptors undergo rapid desensitization and internalization upon agonist challenge (Spampinato et al, 2001, Spampinato et al, 2002, Spampinato et al, 2007). Receptor internalization was also described by other authors (Corbani et al., 2004).
These findings support the idea that NOP receptor, following N/OFQ binding, recruits β-arrestins that promote the internalization of receptors into endosomes. Consequently, receptor internalization becomes dephosphorylated and recycled to the cell surface so that signaling is restored or become targeted for degradation, and the consequent reduction in receptor number, known as receptor down-regulation, contributes to later phases of signal desensitization (Spampinato et al, 2001, Spampinato et al, 2002, Spampinato et al, 2007).
Body temperature is regulated based on a balance between heat production and heat loss; both processes are strictly connected to energy balance that regulates energy intake and consumption (Clapham, 2012, Landsberg, 2012, Richard, 2007, Szekely et al, 2010). Alterations in nutrient supply activate thermoregulatory processes, while changes in thermoregulation cause changes in feeding behavior. Regarding the N/OFQ-NOP receptor system, this topic has been poorly understood. Therefore, we have examined the studies that explored any possible contribution of nociceptin in the regulation of basal body temperature or following treatment with opioids and cannabinoids and have related them to the effects elicited by this peptide on energy balance (i.e., food intake and changes in body weight).
Section snippets
Body temperature regulation
The regulation of body temperature is under the control of hypothalamic structures that integrate afferent and central information necessary to activate appropriate physiological and behavioral responses. In mammals, body temperature is strictly regulated; however, under some conditions, changes in body temperature are beneficial. During infection, an increase in body temperature (i.e., fever) enhances immunologic responses and facilitates the recovery and survival of an individual (Kluger, 1991
Body temperature and energy balance: the role of neuropeptides
Most endogenous neuropeptides seem to exert a coordinated influence on food intake, the metabolic rate and body temperature regulation (Clark, Fregly, 2011, Smitka et al, 2013, Szekely et al, 2004). Anabolic neuropeptides may enhance food intake (orexigenic effect), display hypometabolic effects and tend to reduce body temperature. Foremost among these are neuropeptide Y (Bi et al, 2012, Levine et al, 2004, Williams et al, 2004), orexins (also known as hypocretins; Li et al, 2014, Romanovsky et
N/OFQ: effects on thermoregulation
Yakimova and Pierau (1999) were among the first researchers to report the effects of N/OFQ on the temperature sensitivity of neurons from the preoptic area of the anterior hypothalamus in rat brain slices, whereas the body temperature of male Wistar rats was measured after intrahypothalamic application of N/OFQ. These authors have observed that a low concentration of N/OFQ (1 nM) significantly increases the temperature sensitivity of warm-sensitive neurons of the preoptic area of the anterior
N/OFQ and the regulation of food intake and energy balance
Pomonis et al. (1996) have reported that lateral ventricular administration of N/OFQ moderately increases chow intake. In subsequent studies, mild overeating was also observed following site-specific, but not peripheral, injections of N/OFQ (Polidori et al, 2000, Stratford et al, 1997). Unlike classical opioids, N/OFQ primarily affects eating for energy, not for palatability (Olszewski et al, 2002, Polidori et al, 2000).
Olszewski and Levine (2004) and Olszewski et al. (2010)) have characterized
Concluding remarks
N/OFQ, acting through the NOP receptor, seems to play a relevant role at the hypothalamic level by influencing body temperature control in parallel with the suppression of energy expenditure and increase in body weight. Studies carried out by administering N/OFQ directly into the lateral ventricle of the brain or in knockout mice suggest that N/OFQ contributes to the modulation of the body temperature balance point (Romanovsky, 2007) by causing hypothermia and also by influencing hyperthermia
Conflict of interest
The authors state that there is no conflict of interest about this work.
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