Source: {"pile_set_name": "USPTO Backgrounds"}

Opiates are powerful analgesics (agents used for the treatment of pain), but their use is hampered by non-trivial side effects, tolerance to the analgesic effects, physical dependence resulting in withdrawal effects, and by concerns surrounding the possibility of addiction. By itself, enhanced analgesic efficacy of an opiate can result in opioid sparing, and therefore a reduction in opioid-related side effects. The side effects of opiates include nausea, vomiting, pruritus, insomnia, constipation, sedation and impaired physical function (Ballantyne et al., 2003 N Engl J Med 349:1943-1953).
In many cases, patients taking opioids balance side effects with analgesia, often choosing to tolerate a certain amount of pain so as to avoid side effects. The more severe side effect of respiratory depression can also limit the tolerated dose, and hence the effective analgesia in many patients.
One of the most problematic aspects of opioid therapy is analgesic tolerance with prolonged treatment. Tolerance can be defined as the need for progressively higher doses in order to maintain the same reduction in pain. Although opioid rotation is currently used to minimize tolerance, this approach requires close monitoring due to variable cross-tolerance and side effect profiles among different patients (Fine, 2004 J Pain Palliat Care Pharmacother 18:75-79).
In its most severe form, opioid tolerance can manifest as opioid-induced hyperalgesia; that is, the opiate no longer reduces pain but actually increases or induces pain (Arner et al., 1988 Acta Anaesthesiol Scan 32:253-259; Simonnet et al., 2003 Neuroreport 14:1-7; Fine, 2004 J Pain Palliat Care Pharmacother 18:75-79). This hyperalgesia is clinically similar to the hyperalgesia of neuropathic pain, and in vivo models show that brainstem descending pain facilitation pathways are activated in both syndromes (Vanderah et al., 2001 Pain 92:5-9). Like neuropathic pain, opioid-induced hyperalgesia is extremely difficult to treat and is often a physician's greatest fear in initiating opioid therapy.
Dependence and addiction are also among the greatest fears of pain patients surrounding the use of opiates. Dependence is characterized by physical or psychological withdrawal upon discontinuation of the opiate and can be independent of addiction, which itself is defined by repeated, often self-destructive behaviors focused on obtaining the drug, according to DSM-IV criteria (American Psychiatric Association, 2000).
However, it is still thought that physical dependence, or the desire to avoid withdrawal, contributes to opiate addiction, particularly at later stages of addiction; whereas, a craving for the euphoric effects of opiates can dominate in earlier stages (Koob et al., 1989 Neurosci Biobehav Rev 13:135-140). The somatic withdrawal signs that can occur when opioid therapy is abruptly stopped in physically dependent individuals include agitation, irritability, muscular jerks, abdominal pain, diarrhea, burning sensations, “gooseflesh” and itching (Miser et al., 1986 Am J Dis Child 140:603-604; Heit, 2003 J Pain Palliat Care Phamacother 17:15-29).
Abrupt cessation of opioid treatment can also cause a hyperalgesia, which has also been referred to as opioid-induced hyperalgesia (Li et al., 2001 Anesth Analg 93:204-209). Although patients receiving prolonged opioid analgesic therapy can or can not develop analgesic tolerance, they usually become physically dependent, requiring careful tapering off of the opiate in order to minimize withdrawal effects (Heit, 2003 J Pain Palliat Care Phamacother 17:15-29; Woolf et al., 2004 Curr Opin Investig Drugs 5:61-66).
Opiates produce analgesia by activation of opioid receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Opioid receptors are also involved in the development of the physical and psychological dependence that are important aspects of drug abuse and addiction.
Studies on GPCRs, including opioid receptors, have shown that the third cytoplasmic loop and the carboxyl-terminal tail are very important for signal transduction (Law et al., 2000 Annu Rev Pharmacol Toxicol 40:389-430), regulation (Law and Loh, 1999 J Pharmacol Exp Ther 289:607-624), and internalization of GPCRs (Trapaidze et al., 1996 J Biol Chem 271:29279-29285; Keith et al., 1998 Mol Pharmacol 53:377-384), and are frequently involved in the association of the receptors with other proteins. In addition to G proteins, examples of proteins known to interact with GPCRs are Gprotein-coupled receptor kinases (Pitcher et al., 1998 Annu Rev Biochem 67:653-692), β-arrestins (Lefkowitz, 1998 J Biol Chem 273:18677-18680), PDZ domain-containing adaptor molecules (Milligan and White, 2001 Trends Pharmacol Sci 22:513-518), and scaffolding proteins such as filamin A (Onoprishvilli et al., 2003 Molec Pharmacol 64:1092-1100).
More specifically, opiates produce analgesia by activation of mu (μ) opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. The μ opioid receptor (MOR) preferentially couples to pertussis toxin-sensitive G proteins, Gαi/o (inhibitory/other), and inhibits the adenylyl cyclase/cAMP pathway (Laugwitz et al., 1993 Neuron 10:233-242; Connor et al., 1999 Clin Exp Pharmacol Physiol 26:493-499). The analgesic effects of MOR activation have been predominantly attributed to the Gβγ dimer released from the Gαi/o protein, which activates G protein activated inwardly rectifying potassium (GIRK) channels (Ikeda et al., 2000 Neurosci Res 38:113-116) and inhibits voltage-dependent calcium channels (VDCCs) (Saegusa et al., 2000 Proc Natl Acad Sci USA 97:6132-6137), thereby suppressing cellular activities by hyperpolarization.
Adenylyl cyclase inhibition can also contribute to opioid analgesia, or its activation can contribute to analgesic tolerance. This inhibition is due to overexpression of adenylyl cyclase type 7 in the CNS of mice that leads to more rapid tolerance to morphine (Yoshimura et al., 2000 Mol Pharmacol 58:1011-1016). Additionally, adenylyl cyclase activation has been suggested to elicit analgesic tolerance or tolerance-associated hyperalgesia (Wang et al., 1997 J Neurochem 68:248-254). Although the superactivation of adenylyl cyclase after chronic opioid administration is more often viewed as a hallmark of opioid dependence than as a mediator of tolerance (Nestler, 2001 Am J Addict 10:201-217), both are consequences of chronic opioid administration, and tolerance often worsens dependence. Chronic pain patients who have escalated their opioid dose over time often experience more withdrawal than patients on a constant dose.
An important but underemphasized cellular consequence of chronic opioid treatment is excitatory signaling by opioid receptors in place of the usual inhibitory signaling (Crain et al., 1992 Brain Res 575:13-24; Crain et al., 2000 Pain 84:121-131; Gintzler et al., 2001 Mol Neurobiol 21:21-33; Wang et al., 2005 Neuroscience 135:247-261), possibly as a result of the decreased efficiency of coupling to the native G proteins; that decrease in efficiency being the index of desensitization (Sim et al., 1996 J Neurosci 16:2684-2692). Although the cellular effects of opiates are normally inhibitory, several in vitro studies have demonstrated that opiates can elicit excitatory effects either at low doses (Shen et al., 1989 Brain Res 491:227-242; Crain et al., 1990 Trands Pharmaol Sci 11:77-81) or after chronic exposure (Crain et al., 1992 Brain Res 575:13-24).
In vivo, opiates can cause “paradoxical hyperalgesia” at low doses (Kayser et al., 1987 Brain Res 414:155-157; Kiyatkin, 1989 Int J Neurosci 45:231-246; Crain et al., 2001 Brain Res 888:75-82), or after chronic administration, opioid-induced hyperalgesia (Arner et al., 1988 Acta Anaesthesiol Scan 32:253-259). Although descending facilitation of spinal cord dorsal horn neurons has been implicated in tolerance-associated hyperalgesia (Vanderah et al., 2001 Pain 92:5-9), alterations in opioid receptor signaling also occur with chronic opioid treatment (Shen et al., 1989 Brain Res 491:227-242; Crain et al., 1990 Trends Pharmacol Sci 11:77-81; Crain et al., 1992 Brain Res 575:13-24; Gintzler et al., 2001 Mol Neurobiol 21:21-33) and can contribute to the enhanced firing of descending brainstem projections.
Chronic opioid treatment causes excitatory signaling of opioid receptors via a switch in their G protein coupling from Gi/o to Gs proteins (Wang et al 2005 Neuroscience 135:247-261; Chakrabarti et al., 2005 Mol Brain Res 135:217-224) and by stimulation of adenylyl cyclase II and IV by mu opioid receptor-associated Gβγ dimers (Chakrabarti et al., 1998 Mol Pharmacol 54:655-662; Wang et al., 2005 Neuroscience 135:247-261). The interaction of the Gβγ dimer