β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

“Upon activation, both receptors couple predominantly to Gαi/o proteins (Law et al. 2000; Howlett et al. 2002).”

“The generation of genetic knockout mice has demonstrated that the majority of clinically used opioids including morphine produce their pharmacological effects primarily by activating the MOR (Matthes et al. 1996; Sora et al. 1997; Roy et al. 1998; Kieffer 1999; Kieffer and GaveriauxRuff 2002).”

“Arrestin 2 and arrestin 3 were first discovered for their ability to regulate the β2-adrenergic receptor (Lohse et al. 1990) and, therefore, are also referred to as β-arrestin1 and β-arrestin2, respectively.”

“…antinociception in paradigms that evaluate supra-spinal (hot plate) and spinal (tail flick) antinociceptive responses to a noxious thermal stimulus (Bohn et al. 1999, 2002, 2004; Raehal and Bohn 2011), suggesting that in the absence of the desensitizing effect of the βarrestin2, MOR…”

“2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the analgesic, motor, and psychoactive effects of cannabinoids (Zimmer et al. 1999; Kelly and Chapman 2001; Hohmann et al. 2005; Pertwee 2005; Suplita et al. 2006; Dziaduleqicz et al. 2007).”

“…drugs approved for the treatment of moderate to severe pain, it has been well documented that patients suffering from protracted persistent pain, especially those with cancer or neuropathic pain, often do not receive adequate relief from currently available analgesics (Brennan et al. 2007).”

“The decrease in GABA release promotes disinhibition of the OFF nociceptive neurons and direct inhibition of ON cells, resulting in antinociception (for reviews, see Fields 2004; Rea et al. 2007; Palazzo et al. 2010; Fig.”

“The reduction in antinociceptive tolerance that develops following chronic morphine treatment appears to be due to a loss of β-arrestin2 desensitization of the MOR (Bohn et al. 2000).”

“…throughout the central nervous system and periphery (Lohse et al. 1990; Attramadal et al. 1992; Gurevich and Benovic 2000; Gurevich et al. 2002; Gainetdinov et al. 2004; Bychkov et al. 2012) and have been shown to regulate the activity of MOR and CB1 receptors. β-Arrestins play a multifaceted…”

“There is a rich literature describing MOR and CB1R signaling pathways that lead to antinociceptive responses (for reviews, see Williams et al. 2013; Raehal et al. 2011; Smith et al. 2010) (Fig.”

“2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the analgesic, motor, and psychoactive effects of cannabinoids (Zimmer et al. 1999; Kelly and Chapman 2001; Hohmann et al. 2005; Pertwee 2005; Suplita et al. 2006; Dziaduleqicz et al. 2007).”

“When given acutely, TRV130 also produces less constipation and respiratory suppression compared to mice treated with equi-efficacious doses of morphine (DeWire et al. 2013).”

“Loperamide (clinically used as the antidiarrheal Imodium®) is a peripherally restricted MOR agonist and does not delay colon transit times in the β-arrestin2-KO mice (Raehal et al. 2005).”

“Both β-arrestins are highly expressed in tissues throughout the central nervous system and periphery (Lohse et al. 1990; Attramadal et al. 1992; Gurevich and Benovic 2000; Gurevich et al. 2002; Gainetdinov et al. 2004; Bychkov et al. 2012) and have been shown to regulate the activity of MOR and CB1 receptors.”

“The generation of genetic knockout mice has demonstrated that the majority of clinically used opioids including morphine produce their pharmacological effects primarily by activating the MOR (Matthes et al. 1996; Sora et al. 1997; Roy et al. 1998; Kieffer 1999; Kieffer and GaveriauxRuff 2002).”

“…interactions between the receptor and G proteins even in the continued presence of agonist resulting in diminished G protein-mediated signaling (Zhang et al. 1998; Whistler and von Zastrow 1998; Kovoor et al. 1997, 1998; Bohn et al. 2000; Lowe et al. 2002; Eisinger et al. 2002; Celver et al.…”

“The generation of genetic knockout mice has demonstrated that the majority of clinically used opioids including morphine produce their pharmacological effects primarily by activating the MOR (Matthes et al. 1996; Sora et al. 1997; Roy et al. 1998; Kieffer 1999; Kieffer and GaveriauxRuff 2002).”

“CB1R are widely expressed in the central and peripheral nervous systems (SvÍzenská et al. 2008).”

“While there is evidence demonstrating a modulation of pain responses by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role…”

“While there is evidence demonstrating a modulation of pain responses by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the…”

“Studies of the CB1R also reveal an important role for β-arrestins in desensitizing the agonist-stimulated, phosphorylated CB1R (Sim et al. 1996; Jin et al. 1999; Daigle et al 2008; Nguyen et al. 2012).”

“Studies of the CB1R also reveal an important role for β-arrestins in desensitizing the agonist-stimulated, phosphorylated CB1R (Sim et al. 1996; Jin et al. 1999; Daigle et al 2008; Nguyen et al. 2012).”

“In cell culture studies, these agonists promote both β-arrestin1 and β-arrestin2 interactions with the MOR, whereas morphine weakly and selectively recruits β-arrestin2 (Zhang et al. 2008; Whistler et al 1999; Bohn et al. 2004; Groer et al. 2007; McPherson et al 2010; Molinari et al. 2010).”

“There is a rich literature describing MOR and CB1R signaling pathways that lead to antinociceptive responses (for reviews, see Williams et al. 2013; Raehal et al. 2011; Smith et al. 2010) (Fig.”

“Further, while β-arrestin2-KO mice display prolonged basal antinociceptive response in assays with thermal endpoints such as the tail flick and Hargreaves tests (Bohn et al. 2002; Lam et al 2011), their basal responses in tests of mechanical stimulation using von Frey filaments are similar to their WT littermates (Lam…”

“In cell culture studies, these agonists promote both β-arrestin1 and β-arrestin2 interactions with the MOR, whereas morphine weakly and selectively recruits β-arrestin2 (Zhang et al. 2008; Whistler et al 1999; Bohn et al. 2004; Groer et al. 2007; McPherson et al 2010; Molinari et al. 2010).”

“…et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the analgesic, motor, and psychoactive effects of cannabinoids (Zimmer et al. 1999; Kelly and Chapman 2001; Hohmann et al. 2005; Pertwee 2005; Suplita et al. 2006; Dziaduleqicz et al. 2007).”

“Arrestins 1 and 4 are almost exclusively expressed in rod and cone cells in the visual system (Shinohara et al. 1987; Yamaki et al. 1987; Murakami et al. 1993; Craft et al. 1994) and are therefore referred to as “visual” arrestins.”

“…in paradigms that evaluate supra-spinal (hot plate) and spinal (tail flick) antinociceptive responses to a noxious thermal stimulus (Bohn et al. 1999, 2002, 2004; Raehal and Bohn 2011), suggesting that in the absence of the desensitizing effect of the βarrestin2, MOR responsiveness is enhanced.”

“Arrestins 1 and 4 are almost exclusively expressed in rod and cone cells in the visual system (Shinohara et al. 1987; Yamaki et al. 1987; Murakami et al. 1993; Craft et al. 1994) and are therefore referred to as “visual” arrestins.”

“…of pain responses by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the…”

“…is evidence demonstrating a modulation of pain responses by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most…”

“…a role in determining the fate of MOR and CB1 receptors, from the initiation of clathrin-dependent endocytosis (Jin et al. 1999; Whistler et al. 1999; Celver et al. 2004; Koch et al. 2004; Haberstock-Debic et al. 2005; Walwyn et al. 2006, 2007; Daigle et al. 2008; Groer et al. Handb Exp Pharmacol.”

“Studies of the CB1R also reveal an important role for β-arrestins in desensitizing the agonist-stimulated, phosphorylated CB1R (Sim et al. 1996; Jin et al. 1999; Daigle et al 2008; Nguyen et al. 2012).”

“There are four distinct genes coding for opioid receptors: the mu-, kappa-, and delta-opioid receptors (MOR, KOR, and DOR, respectively) and the opioid-like receptor1 [ORL-1 or the nociceptin receptor (NOP)] (Cox 2012; Pasternak 2013).”

“…β-arrestin1 may play a role in ubiquitinating MOR and facilitating its dephosphorylation and potentially resensitization, while β-arrestin2 is prominently involved in desensitizing the receptor (Kovoor et al. 1997, 1998; Celver et al. 2001; Bohn et al. 2000; Dang et al. 2011; Groer et al. 2011).”

“CB1 receptors have been shown to require β-arrestin2 for CP55940-induced internalization in HEK 293 cells, and the allosteric modulator, ORG27569, was shown to direct CB1 receptors to activating ERK cascades in a β-arrestin1-dependent manner (Ahn et al. 2013).”

“Arrestins 1 and 4 are almost exclusively expressed in rod and cone cells in the visual system (Shinohara et al. 1987; Yamaki et al. 1987; Murakami et al. 1993; Craft et al. 1994) and are therefore referred to as “visual” arrestins.”

“…a modulation of pain responses by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in…”

“…β-arrestin1 may play a role in ubiquitinating MOR and facilitating its dephosphorylation and potentially resensitization, while β-arrestin2 is prominently involved in desensitizing the receptor (Kovoor et al. 1997, 1998; Celver et al. 2001; Bohn et al. 2000; Dang et al. 2011; Groer et al. 2011).”

“…was shown to correlate with decreased CB1R desensitization of G protein coupling in cerebellum, caudal periaqueductal gray, and spinal cord (Nguyen et al. 2012) In addition to tolerance, morphine produces physical dependence, constipation, and respiratory suppression in mice and in humans.”

“…expressed in tissues throughout the central nervous system and periphery (Lohse et al. 1990; Attramadal et al. 1992; Gurevich and Benovic 2000; Gurevich et al. 2002; Gainetdinov et al. 2004; Bychkov et al. 2012) and have been shown to regulate the activity of MOR and CB1…”

“9) to the recruitment of ubiquitin (E3) ligases involved in lysosomal-mediated receptor degradation (Groer et al. 2011; Henry et al. 2012; Malik et al. 2012) (see Chap.”

“In cell culture studies, these agonists promote both β-arrestin1 and β-arrestin2 interactions with the MOR, whereas morphine weakly and selectively recruits β-arrestin2 (Zhang et al. 2008; Whistler et al 1999; Bohn et al. 2004; Groer et al. 2007; McPherson et al 2010; Molinari et al. 2010).”

“3 β-Arrestin-Mediated MOR and CB1R Regulatory Mechanisms β-Arrestins belong to a family of four arrestin proteins (Gurevich and Gurevich 2003).”

“The generation of genetic knockout mice has demonstrated that the majority of clinically used opioids including morphine produce their pharmacological effects primarily by activating the MOR (Matthes et al. 1996; Sora et al. 1997; Roy et al. 1998; Kieffer 1999; Kieffer and GaveriauxRuff 2002).”

“…a role in determining the fate of MOR and CB1 receptors, from the initiation of clathrin-dependent endocytosis (Jin et al. 1999; Whistler et al. 1999; Celver et al. 2004; Koch et al. 2004; Haberstock-Debic et al. 2005; Walwyn et al. 2006, 2007; Daigle et al. 2008; Groer et al. Handb Exp Pharmacol.”

“…a role in determining the fate of MOR and CB1 receptors, from the initiation of clathrin-dependent endocytosis (Jin et al. 1999; Whistler et al. 1999; Celver et al. 2004; Koch et al. 2004; Haberstock-Debic et al. 2005; Walwyn et al. 2006, 2007; Daigle et al. 2008; Groer et al. Handb Exp Pharmacol.”

“…resulting in diminished G protein-mediated signaling (Zhang et al. 1998; Whistler and von Zastrow 1998; Kovoor et al. 1997, 1998; Bohn et al. 2000; Lowe et al. 2002; Eisinger et al. 2002; Celver et al. 2001, 2004; Qiu et al. 2003; Bailey et al. 2004, 2009; Koch et al. 2004; Dang et al. 2009, 2011).”

“Arrestins 1 and 4 are almost exclusively expressed in rod and cone cells in the visual system (Shinohara et al. 1987; Yamaki et al. 1987; Murakami et al. 1993; Craft et al. 1994) and are therefore referred to as “visual” arrestins.”

“LC neurons isolated WT and βarrestin2-KO mice (Quillinan et al 2011).”

“…β-arrestin1 may play a role in ubiquitinating MOR and facilitating its dephosphorylation and potentially resensitization, while β-arrestin2 is prominently involved in desensitizing the receptor (Kovoor et al. 1997, 1998; Celver et al. 2001; Bohn et al. 2000; Dang et al. 2011; Groer et al. 2011).”

“2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the analgesic, motor, and psychoactive effects of cannabinoids (Zimmer et al. 1999; Kelly and Chapman 2001; Hohmann et al. 2005; Pertwee 2005; Suplita et al. 2006; Dziaduleqicz et al. 2007).”

“Fentanylinduced MOR activation of ERK1/2 has also been shown to utilize β-arrestin2 in primary striatal neurons (Macey et al. 2006).”

“…resulting in diminished G protein-mediated signaling (Zhang et al. 1998; Whistler and von Zastrow 1998; Kovoor et al. 1997, 1998; Bohn et al. 2000; Lowe et al. 2002; Eisinger et al. 2002; Celver et al. 2001, 2004; Qiu et al. 2003; Bailey et al. 2004, 2009; Koch et al. 2004; Dang et al. 2009, 2011).”

“The decrease in GABA release promotes disinhibition of the OFF nociceptive neurons and direct inhibition of ON cells, resulting in antinociception (for reviews, see Fields 2004; Rea et al. 2007; Palazzo et al. 2010; Fig.”

“The decrease in GABA release promotes disinhibition of the OFF nociceptive neurons and direct inhibition of ON cells, resulting in antinociception (for reviews, see Fields 2004; Rea et al. 2007; Palazzo et al. 2010; Fig.”

“…β-arrestin1 may play a role in ubiquitinating MOR and facilitating its dephosphorylation and potentially resensitization, while β-arrestin2 is prominently involved in desensitizing the receptor (Kovoor et al. 1997, 1998; Celver et al. 2001; Bohn et al. 2000; Dang et al. 2011; Groer et al. 2011).”

“…et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the analgesic, motor, and psychoactive effects of cannabinoids (Zimmer et al. 1999; Kelly and Chapman 2001; Hohmann et al. 2005; Pertwee 2005; Suplita et al. 2006; Dziaduleqicz et al. 2007).”

“…by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the most pronounced role in mediating the analgesic, motor, and…”

“Both β-arrestins are highly expressed in tissues throughout the central nervous system and periphery (Lohse et al. 1990; Attramadal et al. 1992; Gurevich and Benovic 2000; Gurevich et al. 2002; Gainetdinov et al. 2004; Bychkov et al. 2012) and have been shown to regulate the activity of MOR and CB1…”

“Morphine-induced antinociceptive tolerance in the tail flick test has also been shown to be significantly reduced in rats in which β-arrestin2 expression is knocked down in the spinal cord (Przewlocka et al. 2002; Yang et al. 2011).”

“…resulting in diminished G protein-mediated signaling (Zhang et al. 1998; Whistler and von Zastrow 1998; Kovoor et al. 1997, 1998; Bohn et al. 2000; Lowe et al. 2002; Eisinger et al. 2002; Celver et al. 2001, 2004; Qiu et al. 2003; Bailey et al. 2004, 2009; Koch et al. 2004; Dang et al. 2009, 2011).”

“Investigations of MOR resensitization profiles in LC neurons using the same system revealed that disruption of βarrestin2-mediated receptor endocytosis enhances MOR resensitization rates (Dang et al. 2011).”

“While there is evidence demonstrating a modulation of pain responses by actions at CB2 receptors (Jaggar et al. 1998; Malan et al. 2001; Sokal et al. 2003; Elmes et al. 2004; Hohmann et al. 2004; Ibrahim et al. 2006; LaBuda et al. 2005), CB1 receptors (CB1R) in the central nervous system play the…”

“There are four distinct genes coding for opioid receptors: the mu-, kappa-, and delta-opioid receptors (MOR, KOR, and DOR, respectively) and the opioid-like receptor1 [ORL-1 or the nociceptin receptor (NOP)] (Cox 2012; Pasternak 2013).”

“In an inflammatory pain model in rat, herkinorin reduces formalin-induced flinching to the same degree as morphine when administered at the same dose (10 mg/kg, i.pl.), an effect that is reversed by the opioid antagonist naloxone (Lamb et al. 2012).”

“Interestingly, other agonists, including CP55940, methanandamide, and JWH-073, do not reveal a difference between genotypes in the hypothermia studies (Breivogel et al. 2008).”

“In cell culture studies β-arrestin2 has been shown to act as a scaffolding molecule to promote MOR signaling (Zhang et al. 2008).”

“…preparations derived from the β-arrestin2-KO mice assayed in organ baths to assess morphine’s inhibition of contractility suggest that morphine tolerance develops following repeated morphine treatment in the absence of β-arrestin2, while it does not develop in colon from WT mice (Kang et al. 2012).”

“In contrast, siRNA knockdown of βarrestin1 in rat periaqueductal gray had no effect on morphine-induced antinociception or the development of antinociceptive tolerance in the hot plate test (Li et al. 2009).”

“There is some evidence to support this idea as the transient receptor potential vanilloid 1 (TRPV1) channel, the transducer of thermal and chemical pain transmission, was found to be desensitized by β-arrestin2 (Por et al. 2012, 2013).”

“…resulting in diminished G protein-mediated signaling (Zhang et al. 1998; Whistler and von Zastrow 1998; Kovoor et al. 1997, 1998; Bohn et al. 2000; Lowe et al. 2002; Eisinger et al. 2002; Celver et al. 2001, 2004; Qiu et al. 2003; Bailey et al. 2004, 2009; Koch et al. 2004; Dang et al. 2009,…”

“However, inhibition of ERK1/2 in βarrestin2-KO mice alleviates desensitization, indicating that MOR desensitization in LC neurons is not solely dependent upon β-arrestin2 (Dang et al. 2009).”

“The β-arrestin-mediated effects on opioid constipation appear to be restricted to the periphery, as the genotype-dependent differences are not preserved when WT and β-arrestin2-KO are administered morphine by intracerebroventricular route (Bohn and Raehal 2006).”

“Neurokinin receptors can also be regulated by β-arrestins (Schmidlin et al. 2003); however, no neurokinin receptor-mediated phenotypes have been reported in the β-arrestin2KO mice.”

“9) to the recruitment of ubiquitin (E3) ligases involved in lysosomal-mediated receptor degradation (Groer et al. 2011; Henry et al. 2012; Malik et al. 2012) (see Chap.”

“In cell culture studies, these agonists promote both β-arrestin1 and β-arrestin2 interactions with the MOR, whereas morphine weakly and selectively recruits β-arrestin2 (Zhang et al. 2008; Whistler et al 1999; Bohn et al. 2004; Groer et al. 2007; McPherson et al 2010; Molinari et al. 2010).”

“Morphine-induced antinociceptive tolerance in the tail flick test has also been shown to be significantly reduced in rats in which β-arrestin2 expression is knocked down in the spinal cord (Przewlocka et al. 2002; Yang et al. 2011).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript 2011; Patierno et al. 2011; Ahn et al. 2013) (see Chap.”

“…nervous system and periphery (Lohse et al. 1990; Attramadal et al. 1992; Gurevich and Benovic 2000; Gurevich et al. 2002; Gainetdinov et al. 2004; Bychkov et al. 2012) and have been shown to regulate the activity of MOR and CB1 receptors. β-Arrestins play a multifaceted role in regulating how…”

“There is some evidence to support this idea as the transient receptor potential vanilloid 1 (TRPV1) channel, the transducer of thermal and chemical pain transmission, was found to be desensitized by β-arrestin2 (Por et al. 2012, 2013).”

“An investigation of nociceptive behaviors in drug-naïve animals revealed that β-arrestin2KO mice display longer basal warm water tail flick response latencies (Bohn et al. 2002; Breivogel et al. 2008; Lam et al. 2011; Nguyen et al. 2012), which can be blocked by the opioid antagonists naltrexone or naloxone (Bohn et a…”

“For example, treatment with the JNK inhibitors SP6 or BI78D3 or the PKC inhibitor bisindolylmaleimide VIII prior to morphine reverses the enhanced antinociceptive effect observed in β-arrestin2-KO mice to WT control levels in the tail flick test (Mittal et al. 2012).”

“…a role in determining the fate of MOR and CB1 receptors, from the initiation of clathrin-dependent endocytosis (Jin et al. 1999; Whistler et al. 1999; Celver et al. 2004; Koch et al. 2004; Haberstock-Debic et al. 2005; Walwyn et al. 2006, 2007; Daigle et al. 2008; Groer et al. Handb Exp Pharmacol.”

“Moreover, the antinociceptive effects of morphine in the hot plate test are absent in rats overexpressing βarrestin2 in the periaqueductal gray (Jiang et al. 2006).”

“This contrasts to the absence of robust physiological evidence for a -arrestin signal from the MOR affecting respiratory function (45).”

“…that drugs could be developed that activate m-opioid receptors without activating the arrestin 3 signal transduction cascade and by extrapolation result in less receptor internalization and desensitization, higher analgesic potential, and lower respiratory depression (Raehal and Bohn, 2014).”

“Moreover, as described below, G protein-independent signaling (eg, arrestins) (Raehal and Bohn, 2014; Turu and Hunyady, 2010; Rozenfeld and Devi, 2008) can also be found and are important to consider when talking about CB1 receptor signaling.”