Neuropeptides 50 (2015) 51–56

Contents lists available at ScienceDirect

Neuropeptides j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / n p e p

Role of nociceptin/orphanin FQ in thermoregulation Monica Baiula, Andrea Bedini, Santi M. Spampinato *,1 Department of Pharmacy and Biotechnology, University of Bologna, Italy

A R T I C L E

I N F O

Article history: Received 23 August 2014 Accepted 11 March 2015 Available online 16 March 2015 Keywords: Body temperature Energy balance Food intake Hypothermia Nociceptin Opioids

A B S T R A C T

Nociceptin/Orphanin FQ (N/OFQ) is a 17-amino acid peptide that binds to the nociceptin receptor (NOP). N/OFQ and NOP receptors are expressed in numerous brain areas. The generation of specific agonists, antagonists and receptor-deficient mice or rats has enabled progress in elucidating the biological functions of N/OFQ. These tools have been employed to identify the biological significance of the N/OFQ system and how it interacts with other endogenous systems to regulate several body functions. The present review focuses on the role of N/OFQ in the regulation of body temperature and its relationship with energy balance. Critical evaluation of the literature data suggests that N/OFQ, acting through the NOP receptor, may cause hypothermia by influencing the complex thermoregulatory system that operates as a federation of independent thermoeffector loops to control body temperature at the hypothalamic level. Furthermore, N/OFQ counteracts hyperthermia elicited by cannabinoids or μ-opioid agonists. N/OFQ-induced hypothermia is prevented by ω-conotoxin GVIA, an N-type calcium channel blocker. Hypothermia induced by N/OFQ is considered within the framework of the complex action that this neuropeptide exerts on energy balance. Energy stores are regulated through the complex neural controls exerted on both food intake and energy expenditure. In laboratory rodents, N/OFQ stimulates consummatory behavior and decreases energy expenditure. Taken together, these studies support the idea that N/OFQ contributes to the regulation of energy balance by acting as an “anabolic” neuropeptide as it elicits effects similar to those produced in the hypothalamus by other neuropeptides such as orexins and neuropeptide Y. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Introduction ........................................................................................................................................................................................................................................................... Body temperature regulation .......................................................................................................................................................................................................................... Body temperature and energy balance: the role of neuropeptides ................................................................................................................................................... N/OFQ: effects on thermoregulation ............................................................................................................................................................................................................. N/OFQ and the regulation of food intake and energy balance ............................................................................................................................................................ Concluding remarks ............................................................................................................................................................................................................................................ Conflict of interest ............................................................................................................................................................................................................................................... References ..............................................................................................................................................................................................................................................................

1. 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

* Corresponding author. Department of Pharmacy and Biotechnology, University of Bologna, Irnerio 48, 40126 Bologna, Italy. E-mail address: [email protected] (S.M. Spampinato). 1 Funding: RFO2013 grant obtained from the University of Bologna. http://dx.doi.org/10.1016/j.npep.2015.03.005 0143-4179/© 2015 Elsevier Ltd. All rights reserved.

51 52 52 53 54 54 55 55

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.

52

M. Baiula et al./Neuropeptides 50 (2015) 51–56

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 and 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., 2012; 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, 2002, 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, 2002, 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).

2. 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). In hypoxia, a decrease in body temperature is necessary because it contributes to increased survival primarily through a reduction in metabolism (Buchanan et al., 1991; Malvin and Wood, 1992). The preoptic area of the anterior hypothalamus is one of the major neuronal structures involved in the control of body temperature. In addition to receiving afferent input from peripheral thermoceptors, this area modulates central changes in hypothalamic temperature (Roulant, 1998). Fever is characterized by an alteration of the thermal balance in the complex thermoregulatory system that operates as a federation of independent thermoeffector loops (Romanovsky, 2007), which is induced initially by exogenous pyrogens that induce the synthesis and release of several endogenous pyrogens, including interleukin (IL)-1α, tumor necrosis factor-α, IL-6, and macrophage inflammatory protein (MIP)-1 (Malvin and Wood, 1992; Roth and De Souza, 2001). Endogenous pyrogens seem to influence the activity of neurons in the preoptic area of the anterior hypothalamus through the synthesis and/or release in the central nervous system (CNS) of several mediators, including prostaglandins, corticotrophin releasing factor, and endothelin-1 (Roth and De Souza, 2001; Roth et al., 2006; Zampronio et al., 2000), which produce an elevation in body temperature (Malvin and Wood, 1992; Roth and De Souza, 2001). The cytokine-like properties of Toll-like receptor (TLR) signal transduction provide an explanation by which any microbial product can cause fever by engaging its specific TLR on the vascular network supplying the thermoregulatory center in the anterior hypothalamus. Since fever induced by IL-1, tumor necrosis factor-α, IL-6 or TLR ligands requires cyclooxygenase-2, the production of prostaglandin E2 (PGE2) and the activation of hypothalamic PGE2 receptors provide a unifying mechanism for fever caused by endogenous and exogenous pyrogens (Dinarello, 2004). 3. 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 and 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 al., 2005) and melaninconcentrating hormone (Parker and Bloom, 2012; Shi, 2004). Several catabolic neuropeptides that reduce food intake (anorexigenic effect) may enhance energy expenditure and have a tendency to induce hyperthermia. These include melanocortins (Fan et al., 2005; Pandit et al., 2011), cholecystokinin (Alén et al., 2013; Szelényi, 2010) and corticotropin-releasing factor (Figueiredo et al., 2010; Mastorakos and Zapanti, 2004). Several peptides cannot be included in the anabolic/catabolic groups (e.g., bombesin may suppress food intake and induces hypothermia; Tsushima et al., 2003). The contribution of different neuropeptides in the development or prevention of fever, characterized by an elevated metabolic rate plus a decrease in heat loss, or by the suppression of metabolism

M. Baiula et al./Neuropeptides 50 (2015) 51–56

and/or increased heat loss that causes a sustained low body temperature, remains to be elucidated. Regarding thermoregulation, some neuropeptides may cause a rise in the metabolic rate together with an increase in heat loss. Thus, no change in the core temperature may result, or a rise may be induced in some cases and a fall of core temperature in others (Clark and Fregly, 2011; Szekely et al., 2004). The most general abnormalities of overall energy balance are connected with the regulation of body weight and adiposity. According to this hypothesis, increased activity of anabolic peptides or reduced activity of catabolic peptides may contribute to body weight increase. Neuropeptide abnormalities may also contribute to anorexia (Misra et al., 2006). However, the role of neuropeptides should be also considered in the relationship to body weight changes, thermal adaptation, chronic diseases, nutritional anomalies or fever.

4. 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 hypothalamus, while a higher concentration (100 nM) decreases it; furthermore, in vivo, intrahypothalamic N/OFQ (1 nM; 1 μL/rat) decreases body temperature. This study supports the hypothesis that the specific action of N/OFQ on body temperature seems to be closely related to a specific change in the temperature sensitivity of warm-sensitive neurons from the preoptic area of the anterior hypothalamus. Chen et al. (2001) have explored the effects of N/OFQ on body temperature and whether the opioid system was involved. They reported that intracerebroventricular (i.c.v.) injection of 18 μg of N/OFQ in rats kept in an environmental room at 21 ± 0.3 °C produced a maximal reduction of body temperature of 1 °C (60 min after i.c.v. administration). The rate of hypothermia induced by N/OFQ was less than that elicited by i.c.v. administration of 20 μg NPY (maximum fall of 2 °C) in rats maintained at the ambient temperature of 21 °C (Bouali et al., 1995). Chen et al. (2001) have also observed that i.c.v. administration of N/OFQ decreases hyperthermia elicited by morphine (4 mg/kg, given subcutaneously) but had an additive effect on the hypothermia produced by the kappa-opioid receptor agonist spiradoline. Interestingly, this study also reported that neither the opioid receptor antagonist naloxone nor the kappa opioid receptor antagonist nor-binaltorphimine has an effect on N/OFQ-induced hypothermia. These latter data agree with the study of Meunier et al. (1995), who were among the first scientists to demonstrate that N/OFQ does not bind to opioid receptors. However, it has been shown that N/OFQ can block the antinociception induced by μ-, δ- and κ-opioid agonists in the rat and mouse (Mogil et al., 1996). Taken together, these studies indicate that there may be a functional interaction between opioid receptors and NOP receptors in the brain regulation of body temperature and nociception. Blakley et al. (2004) have confirmed that antisense oligonucleotideinduced down-regulation of the NOP receptor is an effective method for studying the N/OFQ system. Antisense oligonucleotide infusion significantly reduced N/OFQ-stimulated [35S]-GTPgammaS binding in the hypothalamic paraventricular nucleus, prefrontal cortex and septum. Behavioral changes were observed in antisense-treated animals, including a higher body temperature, increased water intake, decreased corticosterone levels, decreased grooming in the open field, increased tail-flick latency, shorter durations on the open arms of

53

the elevated plus maze, and heightened locomotor activity following ethanol administration. Uezu et al. (2004) have reported that NOP receptor knockout mice maintained under a 12:12 h light/dark cycle and at the ambient temperature of 24 ± 1 °C show a higher body temperature only during the light (resting) period (36.5 °C vs. 35.7 °C; n = 9), although spontaneous activity and plasma cortisol levels were essentially the same as those of the control mice. Based on these data, these authors retain that NOP receptor may be involved, not in circadian mechanism but, rather, in thermoregulation. The effects elicited by N/OFQ on body temperature have been extended to other NOP agonists. Teshima et al. (2005) have assayed the NOP agonist 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide (W-212393) to evaluate the circadian body temperature rhythm of rats. W-212393 displays a high affinity for NOP receptors in the rat cerebral cortex and behaves as a full agonist at NOP receptors. This compound, as well as N/OFQ, significantly suppresses the activity of spontaneous firing of suprachiasmatic nucleus neurons in the rat, and the NOP receptor antagonist J-113397 blocks these effects. These results indicate that activation of NOP receptors contributes to the circadian entrainment and W-212393 may represent an interesting agent for the study of circadian rhythms. In mice, the selective NOP receptor agonist SCH 655842 reduces locomotor activity and body temperature; both effects are absent in NOP receptor knockout mice (Lu et al., 2011). Higgins et al. (2001) have studied the non-peptide receptor agonist Ro64-6198 in various tests of rodent neurological function, utilizing NOP receptor knockout mice to examine the pharmacological specificity of this novel NOP agonist. In male mice, effects on balance and motor co-ordination were detected following lower doses (0.3–1 mg/kg intraperitoneally) of Ro64-6198. At higher doses (1–3 mg/kg intraperitoneally), effects on swim behavior and hypothermia were observed. At 10 mg/kg, each effect became more profound, and a severe neurological disturbance appeared, including loss of righting reflex. These effects were absent in NOP receptor knockout mice. Rawls et al. (2007) have used the endpoint of hypothermia to investigate cannabinoid and N/OFQ interactions in conscious animals. First, they proved that cannabinoids produce hypothermia by activating central cannabinoid CB(1) receptors. The i.c.v. administration of N/OFQ also causes significant hypothermia. These authors evaluated the link between cannabinoid CB(1) receptors and NOP receptors in the regulation of body temperature and found that NOP receptor activation is required for cannabinoid-evoked hypothermia, whereas cannabinoid CB(1) receptor activation is not necessary for N/OFQ-induced hypothermia. This interaction is interesting evidence that NOP receptors mediate a cannabinoid-induced effect in conscious animals. By contrast, acetaminophen-induced hypothermia is independent of NOP, opioid or cannabinoid CB1 receptor activation (Corley and Rawls, 2009). The cellular actions of N/OFQ resemble those of μ-, δ-, and κ-opioid receptor agonists – i.e., the activation of inwardly rectifying K+ conductance, inhibition of voltage-activated Ca2+ channel currents (Moran et al., 2000), and blockade of neurotransmitter release. However, unlike opioids, N/OFQ inhibits T-type Ca2+ channel currents (Hawes et al., 2000; Moran et al., 2000). In a previous study (Spampinato et al., 1994), we have reported that the thermoregulatory responses elicited by selective μ-, δ- and κ-opioid receptor agonists are influenced by calcium channel antagonists. Hyperthermia induced by a lower dose of the μ-opioid receptor selective agonist [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO) was changed in rats pretreated with verapamil (a selective L-type calcium channel antagonist) or ω-conotoxin GVIA (an antagonist of the N-type calcium channel) to initial hypothermia with a later rise in body temperature. By contrast, hypothermia

54

M. Baiula et al./Neuropeptides 50 (2015) 51–56

induced by [D-Pen2,D-Pen5]enkephalin (DPDPE) and dynorphin A-(1–17), respectively, selective agonists of δ- and κ-opioid receptors, was blocked by both calcium channel blockers. Recently, we have investigated whether hypothermia observed following i.c.v. administration of N/OFQ is sensitive to calcium-channel blockers, administered by the same route, in the rat. In preliminary experiments (Spampinato et al. unpublished data), we observed that i.c.v. administration of ω-conotoxin GVIA (8 pmol 24 h before) prevents N/OFQ-mediated hypothermia, indicating that N/OFQ elicits hypothermia, in part, through the involvement of N-type calcium channels. In agreement with this idea, Gompf et al. (2005) have described that N/OFQ produces a consistent concentrationdependent inhibition of glutamate-mediated excitatory postsynaptic currents evoked by optic nerve stimulation within the hypothalamic suprachiasmatic nucleus. Furthermore, other studies have reported that N/OFQ modulates ionic conductance by inhibiting N- and L-type calcium channels (Chin et al., 2002; Larsson et al., 2000; Vaughan et al., 2001). Interestingly, Altier et al. (2006) have described that prolonged (≈30 min) exposure of NOP receptors to N/OFQ induces endocytosis of complexes of NOP and N-type calcium channels. This effect is seen selectively for N-type channels and cannot be observed with mu-opioid receptor or angiotensin receptors. According to these authors, this effect may provide a means for the regulation of calcium entry in dorsal root ganglion neurons. However, recently, Murali et al. (2012) did not observe any internalization of N-type calcium channels in either the soma or central nerve terminals of dorsal root ganglion neurons following prolonged exposure to high, desensitizing concentrations of N/OFQ. Further studies are necessary to better address this aspect. Regarding the possible effects elicited by pyrogens on the hypothalamic preproN/OFQ-NOP system, Leggett et al. (2009) reported that lipopolysaccharide (LPS) challenge, known to elevate body temperature at the hypothalamic level, was associated with increased hypothalamic preproN/OFQ transcript expression 4 h after injection compared with controls, whereas no changes in the preproN/OFQ mRNA level in the hippocampus or basal forebrain were detected. By contrast, NOP mRNA levels were not reduced 4 h after LPS. Although it is difficult to interpret these findings in the context of local changes in gene expression after LPS, it may be suggestive of dissociation between preproN/OFQ and NOP gene regulation, at least in terms of the response to LPS seen at this time-point. 5. 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 the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodologies. They have suggested that the N/OFQ-NOP system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially deleterious food. Matsushita et al. (2009) have observed that i.c.v. infusion of N/OFQ significantly increases food intake and body weight both in regular diet- and moderately high-fat diet-fed mice, and these changes were more apparent in the moderately high-fat diet-fed C57BL/6J mice. To investigate whether N/OFQ could change energy metabolism independent of affecting appetite, these authors

performed a pair-feeding study using the moderately high-fat diet-fed mice. As expected, N/OFQ significantly increased food intake and body weight gain in the N/OFQ-infused ad libitum-fed group; however, in the N/OFQ-infused pair-fed group, this neuropeptide did not increase body weight compared with the vehicle group, albeit body fat content was significantly increased in both the N/OFQ-infused ad libitum-fed and pair-fed groups with increased white adipose tissue weight and plasma leptin, insulin, and cholesterol levels. Furthermore, N/OFQ reduced rectal temperature in the pair-fed mice. Thus, it seems that N/OFQ contributes to the development of obesity not only by inducing hyperphagia but also by decreasing energy expenditure possibly linked to body temperature regulation (Suarez, 2012). Maolood and Meister (2010) have used an immunohistochemical approach to investigate the cellular localization and colocalization of N/OFQ-immunoreactive cell bodies in hypothalamic regions containing neurons producing orexigenic or anorexigenic transmitters. In colchicine-treated rats, N/OFQ immunoreactivity was demonstrated in many cell bodies of the arcuate nucleus, paraventricular nucleus and lateral hypothalamic area. Double-labeling assays revealed that N/OFQ was present in some neurons of the ventrolateral part of the arcuate nucleus producing pro-opiomelanocortinderived peptides, as shown by the presence of the anorexigenic peptide alpha-melanocyte-stimulating hormone. Furthermore, N/OFQ was colocalized with cocaine- and amphetamine-regulated transcripts and, sometimes, in neurons of the ventrolateral arcuate nucleus, producing the orexigenic agouti-related peptide. N/OFQ immunoreactivity also occurs in a few tyrosine hydroxylase- or dynorphin-containing neurons in the dorsomedial part of the arcuate nucleus. In parvocellular neurosecretory cells of the paraventricular nucleus of the hypothalamus, N/OFQ was demonstrated in some thyrotropin-releasing hormone- or dynorphin-containing neurons but not in corticotrophin-releasing hormone-producing neurons. Most N/OFQ-positive immunoreactive neurons of the lateral hypothalamus were also positive for orexin and dynorphin but not for the melanin-concentrating hormone. These observations suggest a functional relationship between the above mentioned hypothalamic neuropeptides and N/OFQ in the control of feeding behavior and body weight. In conclusion, the N/OFQ system stimulates consummatory behavior via a dual mechanism: it enhances energy intake and reduces aversive responsiveness. Presumably, N/OFQ shifts the balance between the need to ingest energy and to avoid foods that can rapidly threaten homeostasis through toxicity or changes in osmolality (Costentin, 2003; Szekely et al., 2010; Witkin et al., 2014). 6. 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 elicited by opioids and cannabinoids. Aside from N/OFQ’s involvement in the control of body temperature responses, several studies have implicated that this peptide, through hypothalamic mechanisms, produces hyperphagia and reduces energy expenditure. Taken together, these finding support the idea that nociceptin may contribute to the regulation of energy balance by acting as an “anabolic” neuropeptide because it may produce effects similar to those produced in the hypothalamus by neuropeptide Y (Myers et al., 1996; Szekely et al., 2005) or orexins (Szekely et al., 2002).

M. Baiula et al./Neuropeptides 50 (2015) 51–56

Conflict of interest The authors state that there is no conflict of interest about this work. References Alén, F., Ramírez-López, M.T., Gómez de Heras, R., Rodríguez de Fonseca, F., Orio, L., 2013. Cannabinoid receptors and cholecystokinin in feeding inhibition. Vitam. Horm. 92, 165–196. Altier, C., Khosravani, H., Evans, R.M., Hameed, S., Peloquin, J.B., Vartian, B.A., et al., 2006. ORL1 receptor-mediated internalization of N-type calcium channels. Nat. Neurosci. 9, 31–40. Baiula, M., Bedini, A., Carbonari, G., 2012. Molecular mechanisms mediating nociceptin/orphanin FQ receptor signaling, desensitization and internalization. Curr. Mol. Pharmacol. 5, 372–381. Bi, S., Kim, Y.J., Zheng, F., 2012. Dorsomedial hypothalamic NPY and energy balance control. Neuropeptides 46, 309–314. Blakley, G.G., Pohorecky, L.A., Benjamin, D., 2004. Behavioral and endocrine changes following antisense oligonucleotide-induced reduction in the rat NOP receptor. Psychopharmacology (Berl) 171, 421–428. Bouali, S.M., Fournier, A., St-Pierre, S., Jolicoeur, F.B., 1995. Influence of ambient temperature on the effects of NPY on body temperature and food intake. Pharmacol. Biochem. Behav. 50, 473–475. Buchanan, T.A., Cane, P., Eng, C.C., Sipos, G.F., Lee, C., 1991. Hypothermia is critical for survival during prolonged insulin-induced hypoglycemia in rats. Metabolism 40, 330–334. Chen, X., McClatchy, D.B., Geller, E.B., Liu-Chen, L., Tallarida, R.J., Adler, M.W., 2001. Possible mechanism of hypothermia induced by intracerebroventricular injection of orphanin FQ/nociceptin. Brain Res. 904, 252–258. Chin, J.H., Harris, K., MacTavish, D., Jhamandas, J.H., 2002. Nociceptin/orphanin FQ modulation of ionic conductances in rat basal forebrain neurons. J. Pharmacol. Exp. Ther. 303, 188–195. Clapham, J.C., 2012. Central control of thermogenesis. Neuropharmacology 63, 111–123. Clark, W.G., Fregly, M.J., 2011. Evidence for roles of brain peptides in thermoregulation. Compr. Physiol. 139–153. Connor, M., Yeo, A., Henderson, G., 1996. The effect of nociceptin on Ca2+ channel current and intracellular Ca2+ in the SH-SY5Y human neuroblastoma cell line. Br. J. Pharmacol. 118, 205–207. Corbani, M., Gonindard, C., Meunier, J.C., 2004. Ligand-regulated internalization of the opioid receptor-like 1: a confocal study. Endocrinology 145, 2876–2885. Corley, G., Rawls, S.M., 2009. Opioid, cannabinoid CB1 and NOP receptors do not mediate APAP-induced hypothermia in rats. Pharmacol. Biochem. Behav. 92, 503–507. Costentin, J., 2003. Physiological and neurobiological aspects of eating. Bull. Acad. Natl Med. 187, 1367–1376. Dinarello, C.A., 2004. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J. Endotoxin Res. 10, 201–222. Fan, W., Voss-Andreae, A., Cao, W.H., Morrison, S.F., 2005. Regulation of thermogenesis by the central melanocortin system. Peptides 26, 1800–1813. Figueiredo, M.J., Fabricio, A.S., Machado, R.R., Melo, M.C., Soares, D.M., Souza, G.E., 2010. Increase of core temperature induced by corticotropin-releasing factor and urocortin: a comparative study. Regul. Pept. 165, 191–199. Gompf, H.S., Moldavan, M.G., Irwin, R.P., Allen, C.N., 2005. Nociceptin/orphanin FQ (N/OFQ) inhibits excitatory and inhibitory synaptic signaling in the suprachiasmatic nucleus (SCN). Neuroscience 132, 955–965. Hawes, B.E., Graziano, M.P., Lambert, D.G., 2000. Cellular actions of nociceptin: transduction mechanisms. Peptides 21, 961–967. Higgins, G.A., Grottick, A.J., Ballard, T.M., Richards, J.G., Messer, J., Takeshima, H., et al., 2001. Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function. Neuropharmacology 41, 97–107. Hur, E.M., Kim, K.T., 2002. G protein-coupled receptor signalling and cross-talk: achieving rapidity and specificity. Cell. Signal. 14, 397–405. Kluger, M.J., 1991. Fever: role of pyrogens and cryogens. Physiol. Rev. 71, 93–127. Landsberg, L., 2012. Core temperature: a forgotten variable in energy expenditure and obesity? Obes. Rev. 13 (Suppl. 2), 97–104. Larsson, K.P., Olsen, U.B., Hansen, A.J., 2000. Nociceptin is a potent inhibitor of N-type Ca(2+) channels in rat sympathetic ganglion neurons. Neurosci. Lett. 296, 121–124. Leggett, J.D., Dawe, K.L., Jessop, D.S., Fulford, A.J., 2009. Endogenous nociceptin/ orphanin FQ system involvement in hypothalamic-pituitary-adrenal axis responses: relevance to models of inflammation. J. Neuroendocrinol. 21, 888–897. Letchworth, S.R., Mathis, J.P., Rossi, G.C., Bodnar, R.J., Pasternak, G.W., 2000. Autoradiographic localization of 125 I[Tyr(14)]orphanin FQ/nociceptin and 125I[Tyr(10)]orphanin FQ/nociceptin(1–11) binding sites in rat brain. J. Comp. Neurol. 423, 319–329. Levine, A.S., Jewett, D.C., Cleary, J.P., Kotz, C.M., Billington, C.J., 2004. Our journey with neuropeptide Y: effects on ingestive behaviors and energy expenditure. Peptides 25, 505–510. Levitt, E.S., Purington, L.C., Traynor, J.R., 2011. Gi/o-coupled receptors compete for signaling to adenylyl cyclase in SH-SY5Y cells and reduce opioid-mediated cAMP overshoot. Mol. Pharmacol. 79, 461–471. Li, J., Hu, Z., de Lecea, L., 2014. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332–350.

55

Lu, S.X., Higgins, G.A., Hodgson, R.A., Hyde, L.A., Del Vecchio, R.A., Guthrie, D.H., et al., 2011. The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): comparison of efficacy and side effects across rodent species. Eur. J. Pharmacol. 661, 63–71. Malvin, G.M., Wood, S.C., 1992. Behavioral hypothermia and survival of hypoxic protozoans Paramecium caudatum. Science 255, 1423–1425. Maolood, N., Meister, B., 2010. Nociceptin/orphanin FQ peptide in hypothalamic neurones associated with the control of feeding behaviour. J. Neuroendocrinol. 22, 75–82. Mastorakos, G., Zapanti, E., 2004. The hypothalamic-pituitary-adrenal axis in the neuroendocrine regulation of food intake and obesity: the role of corticotropin releasing hormone. Nutr. Neurosci. 7, 271–280. Matsushita, H., Ishihara, A., Mashiko, S., Tanaka, T., Kanno, T., Iwaasa, H., et al., 2009. Chronic intracerebroventricular infusion of nociceptin/orphanin FQ produces body weight gain by affecting both feeding and energy metabolism in mice. Endocrinology 150, 2668–2673. Meunier, J.C., 1997. Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor. Eur. J. Pharmacol. 340, 1–15. Meunier, J.C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., et al., 1995. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377, 532–535. Misra, M., Miller, K.K., Tsai, P., Gallagher, K., Kin, A., Lee, N., et al., 2006. Elevated peptide YY levels in adolescent girls with anorexia nervosa. J. Clin. Endocrinol. Metab. 91, 1027–1033. Mogil, J.S., Pasternak, G.W., 2001. The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol. Rev. 53, 381–415. Mogil, J.S., Grisel, J.E., Reinscheid, R.K., Civelli, O., Belknap, J.K., Grandy, D.K., 1996. Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75, 333–337. Moran, T.D., Abdulla, F.A., Smith, P.A., 2000. Cellular neurophysiological actions of nociceptin/orphanin FQ. Peptides 21, 969–976. Murali, S.S., Napier, I.A., Rycroft, B.K., Christie, M.J., 2012. Opioid-related (ORL1) receptors are enriched in a subpopulation of sensory neurons and prolonged activation produces no functional loss of surface N-type calcium channels. J. Physiol. 590 (Pt 7), 1655–1667. Myers, R.D., Lankford, M.F., Roscoe, A.K., 1996. Neuropeptide Y perfused in the preoptic area of rats shifts extracellular efflux of dopamine, norepinephrine, and serotonin during hypothermia and feeding. Neurochem. Res. 21, 637–648. Neal, C.R., Jr., Mansour, A., Reinscheid, R., Nothacker, H.P., Civelli, O., Watson, S.J., 1999. Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J. Comp. Neurol. 406, 503–547. Olszewski, P.K., Levine, A.S., 2004. Characterization of influence of central nociceptin/ orphanin FQ on consummatory behavior. Endocrinology 145, 2627–2632. Olszewski, P.K., Grace, M.K., Sanders, J.B., Billington, C.J., Levine, A.S., 2002. Effect of nociceptin/orphanin FQ on food intake in rats that differ in diet preference. Pharmacol. Biochem. Behav. 73, 529–535. Olszewski, P.K., Grace, M.K., Fard, S.S., Le Greves, M., Klockars, A., Massi, M., et al., 2010. Central nociceptin/orphanin FQ system elevates food consumption by both increasing energy intake and reducing aversive responsiveness. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R655–R663. Pandit, R., de Jong, J.W., Vanderschuren, L.J., Adan, R.A., 2011. Neurobiology of overeating and obesity: the role of melanocortins and beyond. Eur. J. Pharmacol. 660, 28–42. Parker, J.A., Bloom, S.R., 2012. Hypothalamic neuropeptides and the regulation of appetite. Neuropharmacology 63, 18–30. Polidori, C., De Caro, G., Massi, M., 2000. The hyperphagic effect of nociceptin/orphanin FQ in rats. Peptides 21, 1051–1062. Pomonis, J.D., Billington, C.J., Levine, A.S., 1996. Orphanin FQ, agonist of orphan opioid receptor ORL1, stimulates feeding in rats. Neuroreport 8, 369–371. Rawls, S.M., Schroeder, J.A., Ding, Z., Rodriguez, T., Zaveri, N., 2007. NOP receptor antagonist, JTC-801, blocks cannabinoid-evoked hypothermia in rats. Neuropeptides 41, 239–247. Reinscheid, R.K., Nothacker, H.P., Bourson, A., Ardati, A., Henningsen, R.A., Bunzow, J.R., et al., 1995. Orphanin FQ: a neuropeptide that activates an opioid like G protein-coupled receptor. Science 270, 792–794. Richard, D., 2007. Energy expenditure: a critical determinant of energy balance with key hypothalamic controls. Minerva Endocrinol. 32, 173–183. Romanovsky, A.A., 2007. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R37–R46. Romanovsky, A.A., Almeida, M.C., Aronoff, D.M., Ivanov, A.I., Konsman, J.P., Steiner, A.A., et al., 2005. Fever and hypothermia in systemic inflammation: recent discoveries and revisions. Front. Biosci. 10, 2193–2216. Roth, J., De Souza, G.E., 2001. Fever induction pathways: evidence from responses to systemic or local cytokine formation. Braz. J. Med. Biol. Res. 34, 301–314. Roth, J., Rummel, C., Barth, S.W., Gerstberger, R., Hubschle, T., 2006. Molecular aspects of fever and hyperthermia. Neurol. Clin. 24, 421–439. Roulant, J.A., 1998. Hypothalamic neurons. Mechanisms of sensitivity to temperature. Ann. N. Y. Acad. Sci. 856, 108–115. Shi, Y., 2004. Beyond skin color: emerging roles of melanin-concentrating hormone in energy homeostasis and other physiological functions. Peptides 25, 1605–1611. Smitka, K., Papezova, H., Vondra, K., Hill, M., Hainer, V., Nedvidkova, J., 2013. The role of “mixed” orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissuegut-brain axis: relevance to food intake and nutritional status in patients

56

M. Baiula et al./Neuropeptides 50 (2015) 51–56

withanorexia nervosa and bulimia nervosa. Int. J. Endocrinol. 483145. doi:10.1155/ 2013/483145. Spampinato, S., Speroni, E., Govoni, P., Pistacchio, E., Romagnoli, C., Murari, G., et al., 1994. Effect of omega-conotoxin and verapamil on antinociceptive, behavioural and thermoregulatory responses to opioids in the rat. Eur. J. Pharmacol. 254, 229–238. Spampinato, S., Di Toro, R., Qasem, A.R., 2001. Nociceptin-induced internalization of the ORL1 receptor in human neuroblastoma cells. Neuroreport 12, 3159–3163. Spampinato, S., Di Toro, R., Alessandri, M., Murari, G., 2002. Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells. Cell. Mol. Life Sci. 59, 2172–2183. Spampinato, S., Baiula, M., Calienni, M., 2007. Agonist-regulated internalization and desensitization of the human nociceptin receptor expressed in CHO cells. Curr. Drug Targets 8, 137–146. Stratford, T.R., Holahan, M.R., Kelley, A.E., 1997. Injections of nociceptin into nucleus accumbens shell or ventromedial hypothalamic nucleus increase food intake. Neuroreport 8, 423–426. Suarez, R.K., 2012. Energy and metabolism. Compr. Physiol. 2, 2527–2540. Szekely, M., Petervari, E., Balasko, M., Hernadi, I., Uzsoki, B., 2002. Effects of orexins on energy balance and thermoregulation. Regul. Pept. 104, 47–53. Szekely, M., Petervari, E., Szelenyi, Z., 2004. Orexigenic vs. anorexigenic peptides and feeding status in the modulation of fever and hypothermia. Front. Biosci. 9, 2746–2763. Szekely, M., Petervari, E., Pakai, E., Hummel, Z., Szelenyi, Z., 2005. Acute, subacute and chronic effects of central neuropeptide Y on energy balance in rats. Neuropeptides 39, 103–115.

Szekely, M., Petervari, E., Balasko, M., 2010. Thermoregulation, energy balance, regulatory peptides: recent developments. Front. Biosci. (Schol. Ed.) 2, 1009–1046. Szelényi, Z., 2010. Cholecystokinin: role in thermoregulation and other aspects of energetics. Clin. Chim. Acta 411, 329–335. Teshima, K., Minoguchi, M., Tounai, S., Ashimori, A., Eguchi, J., Allen, C.N., et al., 2005. Nonphotic entrainment of the circadian body temperature rhythm by the selective ORL1 receptor agonist W-212393 in rats. Br. J. Pharmacol. 146, 33–40. Tsushima, H., Mori, M., Fujiwara, N., Moriyama, A., 2003. Pharmacological characteristics of bombesin receptor mediating hypothermia int he central nervous system of rats. Brain Res. 969, 88–94. Uezu, K., Sei, H., Sano, A., Toida, K., Suzuki-Yamamoto, T., Houtani, T., et al., 2004. Lack of nociceptin receptor alters body temperature during resting period in mice. Neuroreport 15, 751–755. Vaughan, C.W., Connor, M., Jennings, E.A., Marinelli, S., Allen, R.G., Christie, M.J., 2001. Actions of nociceptin/orphanin FQ and other prepronociceptin products on rat rostral ventromedial medulla neurons in vitro. J. Physiol. 534 (Pt 3), 849–859. Williams, G., Cai, X.J., Elliott, J.C., Harrold, J.A., 2004. Anabolic neuropeptides. Physiol. Behav. 81, 211–222. Witkin, J.M., Statnick, M.A., Rorick-Kehn, L.M., Pintar, J.E., Ansonoff, M., Chen, Y., et al., 2014. The biology of nociceptin/orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharmacol. Ther. 141, 283–299. Yakimova, K.S., Pierau, F.K., 1999. Nociceptin/orphanin FQ: effects on thermoregulation in rats. Methods Find. Exp. Clin. Pharmacol. 21, 345–352. Zampronio, A.R., Melo, M.C., Hopkins, S.J., De Souza, G.E., 2000. Involvement of CRH in fever induced by a distinct pre-formed pyrogenic factor (PFPF). Inflamm. Res. 49, 473–479.