Evidence for a Selective Role of the δ-Opioid Agonist [8R-(4bS*,8aα,8aβ,12bβ)]7,10-Dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline Hydrochloride (SB-235863) in Blocking Hyperalgesia Associated with Inflammatory and Neuropathic Pain Responses

Abstract

The specific involvement of the ␦-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant ␦-opioid agonist. [8R-(4bS*,8a␣,8a␤,12b␤)]7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) is a new pyrrolomorphinan with high affinity (K i ϭ 4.81 Ϯ 0.39 nM) for the ␦-opioid receptor, full agonist activity, and binding selectivity versus the -and -opioid receptors of 189-fold and 52-fold, respectively. Perorally administered SB-236863 was inactive in the rat tail-flick and hot-plate tests of acute pain response, but potently reversed thermal hyperalgesia in rats resulting from a carrageenan-induced inflammatory response. This activity could be blocked by the ␦-opioid antagonist naltrindole (3 mg/kg s.c.), but selective -and -opioid antagonists were ineffective. Naltrindole (1 g i.c.v.) also blocked the activity of 10 mg/kg (p.o.) SB-235863, showing that the compound activates ␦-opioid receptor sites in the central nervous system. SB-235863 was additionally effective at reversing chronic hyperalgesia in the Seltzer rat model of partial sciatic nerve ligation after peroral administration. These data show that the ␦-opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects ofand -opioid receptor activation (slowing of gastrointestinal transit and motor incoordination, respectively) were not observed after administration of 70 mg/kg (p.o.) SB-235863, nor was evoked seizure activity affected. These results suggest a selective and limited role of ␦-opioid receptors in the modulation of nociception.Localization studies of the ␦-opioid receptor (Peckys and Landwehrmeyer, 1999) reveal its expression in areas associated with pain signaling, and suggest its likely involvement in the control of nociception. The ␦-opioid receptor is located in subregions of both ascending and descending pain pathways, and can control the release of neurotransmitters and peptides involved in nociceptive signaling (Suarez-Roca and Maixner, 1992;Lupica, 1995). The relatively restricted localArticle, publication date, and citation information can be found at

Antidepressant-like Effects of δ Opioid Receptor Agonists in Animal Models

“…As supported these notion, recent studies on δ opioid receptor agonists (Fig. 1 ), such as (–)–NIH 11082 [64], SB-235863 [67], ADL5859 [40], ADL5747 [68], JNJ-20788560 [69] and AZD2327 [41], KNT-127 [62], have failed to demonstrate convulsive effects with these agonists. We demonstrated that KNT-127 produced no convulsions or catalepsy, even at a much higher dose (100 mg/kg) than those required for antidepressant-like and antinociceptive effects in mice [62].…”

“…Interestingly, both non-convulsive δ opioid receptor agonist KNT-127 [62] and SB-235863 [67] has a characteristic morphinan chemical structure (Fig. 1 ), which was designed according to an extension of the message–address concept proposed by Portoghese (1989) [70].…”

New targets for neuropathic pain therapeutics

“…Recent focus has shifted to the δ-opioid receptor (DOR) because selective agonists may provide efficacy without many of the side effects associated with morphine treatment. Systemic administration of the selective agonist SB-235863 reverses thermal hyperalgesia resulting from sciatic nerve ligation without any effect on gastrointestinal transit or motor coordination [82]. Systemic administration of DOR agonists has little effect on acute pain, but results in potent analgesia following morphine pretreatment or following inflammatory stimuli [83].…”

The delta opioid receptor: an evolving target for the treatment of brain disorders

“…In this case, analgesic tolerance resulted from receptor internalization-independent mechanisms that occurred specifically in pain pathways ([23] and Figure 1). In other tolerance studies, SNC80 induced differential tolerance for convulsant, locomotor, and antidepressant responses [24], and the novel delta opioid agonists SB-235863 and JNJ-20788560 did not induce analgesic tolerance in animal models of chronic pain [25,26]. In the future, the exact relationship between agonist-induced internalization, behavioral effects of agonists and the distinct forms of tolerance should be determined for a number of different delta opioid agonists (see Table 1), in order to establish whether in vivo internalization has any predictive value for drug efficacy in clinically relevant experimental settings.…”

“…More recently, the identification of several novel systemically active delta opioid agonists has confirmed the potential of delta opioid receptors as a useful target for chronic pain (see [4,22,25,26,54-59] and Table 1) and some of these drugs are under clinical trials (http://clinicaltrials.gov/ct2/results?term=“delta+opioid”). …”