Sodium Channel Blocking Actions of the κ-Opioid Receptor Agonist U50,488 Contribute to Its Visceral Antinociceptive Effects

Abstract

. Sodium channel blocking actions of the -opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects. J Neurophysiol 87: 1271-1279, 2002; 10.1152/jn.00624.2001. The goal of the present study was to determine whether the -opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic -ORA (Ϯ)-trans U50,488, its enantiomers (Ϫ)-trans (1S,2S)-U50,488 and non -ORA (ϩ)-trans (1R,2R)-U50,488, and/or its diastereomer (Ϫ)-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was: (1S,2S)-U50,488 Ͼ U50,488 Ͼ Ͼ (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively. The mean inhibitory doses of these drugs were not different (range: 6.6 -10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the -ORAs dynorphin (1-13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor-mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein-mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions. I N T R O D U C T I O NThe mechanisms and modulation of visceral pain have been extensively examined using colorectal distension (CRD) as a noxious visceral stimulus. Previous studies employing CRD have documented the ability of -opioid receptor agonists (ORAs) like U50,488 to attenuate pseudaffective visceromotor and cardiovascular responses to noxious CRD following their systemic, but not intrathecal administration (Danzebrink et al. 1995; Harada et al. 1995a,b). A peripheral, visceral antinociceptive action of U50,488 has been demonstrated. U50,488 was shown to dose dependently inhibit responses of mechanosensitive pelvic nerve afferent fibers to noxious colorectal or urinary bladder distension in the rat Su et al. 1997a,b). This inhibition could not be completely antagonized by very high doses of naloxone or by two -opioid receptor-selective antagonists, nor-Binaltorphimine dihydrochloride (nor-BNI) and DIPPA. Furthermore, ...

Nonopioid Actions of U50,488 Enantiomers Contribute to Their Peripheral Cutaneous Antinociceptive Effects

“…This hypothesis was directly addressed by investigating the effects of (Ϫ)-(1S,2S)-U50,488 and (ϩ)-(1R,2R)-U50,488 on voltage-gated sodium currents in colon sensory neurons in the S1 dorsal root ganglion. Both U50,488 enantiomers decreased voltage-gated sodium currents with comparable potencies even in the presence of opioid receptor antagonism (Su et al, 2002). Such findings demonstrate that the two U50,488 enantiomers have comparable potency in blocking voltage-gated sodium channels, but drastically different actions on the KOR.…”

“…Subsequent electrophysiological studies confirmed that this nonopioid effect of U50,488 was due to a direct blockade of voltage-gated sodium channels in cardiac myocytes (Pugsley et al, 1993(Pugsley et al, , 1994. The sodium channel blocking actions of -ORAs have been replicated in hippocampal CA3 neurons (Alzheimer and Bruggencate, 1990), neuroblastoma cells (Zhu and Im, 1992) and more recently in primary sensory neurons in the dorsal root ganglion (Su et al, 2002). Another line of evidence for opioid receptor-independent blockade of sodium channels by -ORAs such as U50,488 derives from experiments using heterogeneous expression of sodium channels in oocytes (Pugsley et al, 2000).…”

“…For example, the antiarrhythmic efficacy of arylacetamide was maintained when enantiomeric pairs such as (ϩ)-PD 129,290 (which lacks affinity for the KOR) and (Ϫ)-PD 129,289 (which has high affinity for the KOR) were examined (Pugsley et al, 1993), giving further support to the notion that these cardiac effects were not mediated by the KOR, but by sodium channel blockade. In studies of visceral nociception, systemically administered (Ϯ)-trans-U50,488, (ϩ)-(1R,2R)-U50,488, and (Ϫ)-(1S,2S)-U50,488 produced dose-dependent antinociception and also dose dependently attenuated responses of decentralized pelvic nerve afferent fibers to noxious colon distension, the latter by a KOR-independent mechanism, suggesting contribution of sodium channel blockade by a nonopioid mechanism (Su et al, 2002). This hypothesis was directly addressed by investigating the effects of (Ϫ)-(1S,2S)-U50,488 and (ϩ)-(1R,2R)-U50,488 on voltage-gated sodium currents in colon sensory neurons in the S1 dorsal root ganglion.…”

“…A series of experiments have established that the cardiovascular effects of -ORAs such as antiarrhythmia and hypotension occur due to their sodium channel blocking actions in cardiac myocytes (Pugsley et al, 1993(Pugsley et al, , 1994. Such actions of -ORAs have also been demonstrated in hippocampal CA3 neurons (Alzheimer and Bruggencate, 1990), neuroblastoma cells (Zhu and Im, 1992), primary sensory neurons in the dorsal root ganglia (Su et al, 2002), and in oocytes heterogeneously expressing sodium channels (Pugsley et al, 2000). The blockade of voltage-gated sodium channels in these studies was opioid-receptor independent, as verified by use of opioid receptor antagonists.…”

“…In contrast, the (ϩ)-trans-(1R,2R)-U50,488 enantiomer has insignificant affinity toward the KOR (K d ϭ 299 nM) and is without effect in KOR-mediated antinociceptive assays. Although U50,488 and both its enantiomers each have a distinct opioid pharmacology, they display comparable potencies in producing a block of voltagegated sodium channels by a nonopioid mechanism (Pugsley et al, 1993;Su et al, 2002).…”