Antiallodynic Effects of Loperamide and Fentanyl against Topical Capsaicin-Induced Allodynia in Unanesthetized Primates

Abstract

Capsaicin produces thermal allodynia in animals and humans by acting as an agonist at vanilloid receptor subtype 1 [VR1; also known as transient receptor potential vanilloid type 1 (TRPV1)]. VR1 receptors are widely distributed in the periphery (e.g., on primary afferent neurons). These studies examined the ability of loperamide (0.1-1 mg/kg s.c.; a -opioid agonist that is peripherally selective after systemic administration), in preventing and reversing thermal allodynia caused by topical capsaicin (0.004 M) in rhesus monkeys, within a tail withdrawal assay (n ϭ 4; 38°C and 42°C; normally non-noxious thermal stimuli). The effects of loperamide were compared with those of the centrally penetrating -agonist, fentanyl (0.0032-0.032 mg/kg s.c.). We also characterized the allodynic effects of the endogenous VR1 agonist ("endovanilloid"), N-oleoyldopamine (OLDA; 0.0013-0.004 M). In this model, loperamide and fentanyl produced dose-dependent prevention of capsaicin-induced allodynia, whereas only fentanyl produced robust reversal of ongoing allodynia. Antagonism experiments with naltrexone (0.1 mg/kg s.c.) or its analog, methylnaltrexone (0.32 mg/kg s.c.), which does not readily cross the blood-brain barrier, suggest that the antiallodynic effects of loperamide and fentanyl were predominantly mediated by peripherally and centrally located -receptors, respectively. Loperamide and fentanyl (1 mg/kg and 0.032 mg/kg, respectively) also prevented OLDA (0.004 M)-induced allodynia. Up to the largest dose studied, loperamide was devoid of thermal antinociceptive effects at 48°C (a noxious thermal stimulus, in the absence of capsaicin). By contrast, fentanyl (0.01-0.032 mg/kg) caused dose-dependent antinociception in this sensitive thermal antinociceptive assay (a presumed centrally mediated effect). These studies show that loperamide, acting as a peripherally selective -agonist after systemic administration, can prevent capsaicin-induced thermal allodynia in primates in vivo, in the absence of thermal antinociceptive effects.Capsaicin is the main pungent component of "hot" chili peppers; this compound can produce thermal allodynia in experimental animals and humans, by acting as an agonist at vanilloid receptors subtype 1 (VR1; also known as TRPV1 receptors) (Caterina and Julius, 2001). VR1 receptors are widely distributed in the periphery and in the central nervous system (Mezey et al., 2000). With respect to cutaneous tissues, as relevant to these studies, VR1 receptors are located in several structures, including primary afferent neurons and keratinocytes (Caterina and Julius, 2001;Southall et al., 2003). Vanilloid VR1 receptors are sensitized and/or up-regulated during conditions associated with tissue damage, including noxious heat, low pH, inflammation, or neuropathic insults (Caterina and Julius, 2001;Hudson et al., 2001;Ji et al., 2002). As such, capsaicin-induced allodynia and its modulation are prominent models in the study of pain mechanisms in vivo and their pharmacological blockade.Studies in rodents have...

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

“…The allodynic effects of capsaicin peak at 15 min after removal of the capsaicin bandage, and this is the time at which to measure the tail-withdrawal latency in 46°C water to evaluate the antiallodynic effects of the test compound. This allodynic response was manifested as reduced tail-withdrawal latency from a maximum value of 20 s to ∼2-3 s in 46°C water (21,61).…”

“…Capsaicin-induced thermal allodynia. At multiple time points after s.c. administration of BU08028, 0.3 mL of capsaicin at 1.2 mg/mL was administered topically via a bandage attached on the terminal 3-5 cm of the tail for 15 min (61). The allodynic effects of capsaicin peak at 15 min after removal of the capsaicin bandage, and this is the time at which to measure the tail-withdrawal latency in 46°C water to evaluate the antiallodynic effects of the test compound.…”

Species Comparison and Pharmacological Characterization of Human, Monkey, Rat, and Mouse TRPA1 Channels

“…Our findings suggest that rhesus monkey could act as a surrogate species for humans in preclinical studies. Various rhesus monkey models have been described in the literature, including ones for thermal nociception (Stevenson et al, 2003), capsaicin-induced thermal allodynia (Butelman et al, 2004) and hyperalgesia (Hu et al, 2010), and carrageenan-induced thermal hyperalgesia (Ko and Lee, 2002). Testing hTRPA1 antagonists for efficacy in rhesus monkey, instead of conventional rat/mouse models, could overcome the serious challenge of species-specific differences and possibly facilitate the development of a selective TRPA1 antagonist for the treatment of pain and neurogenic inflammation.…”

Antinociceptive Interactions between Mu-Opioid Receptor Agonists and the Serotonin Uptake Inhibitor Clomipramine in Rhesus Monkeys: Role of Mu Agonist Efficacy

“…Insofar as motor impairment and nonspecific behavioral suppression may confound measures of thermal nociception, we therefore determined clomipramine-mu agonist interactions in an assay of schedule-controlled responding for comparison with antinociceptive interactions (Stevenson et al, 2003;Negus et al, 2008Negus et al, , 2009. Finally, to assess the generality of antinociceptive interactions to a model of inflammatory pain, clomipramine-nalbuphine interactions were also examined in an assay of capsaicin-induced thermal allodynia (Negus et al, 1993;Butelman et al, 2004;Do Carmo et al, 2008). We hypothesized that clomipramine would selectively enhance the antinociceptive and antiallodynic effects of mu agonists.…”