The naturally occurring hallucinogen salvinorin A produces discriminative stimulus effects similar to those of a high efficacy kappa-agonist in non-human primates.

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...

Topically administered capsaicin produces thermal allodynia, and this effect has been used to investigate pain transduction and its pharmacological modulation. This study investigated the parameters of topical capsaicin-induced thermal allodynia in unanesthetized rhesus monkeys and its pharmacological modulation by centrally acting compounds [a -opioid agonist: ,593); and noncompetitive N-methyl-D-aspartate (NMDA) antagonists: ketamine and MK-801 (dizocilpine)]. Rhesus monkeys (n ϭ 4) were studied within the warm water tail withdrawal assay (20-s maximum latency), using thermal stimuli that are normally not noxious (38 and 42°C). Capsaicin was applied topically on the tail (0.0013 and 0.004 M capsaicin solution on a 1-cm 2 patch; 15-min contact). Topical capsaicin produced concentration-dependent thermal allodynia in both temperatures, robustly detected 15 to 90 min after topical capsaicin removal. A similar allodynic profile was observed with topical administration of the "endovanilloid" N-arachidonoyl-dopamine. The -agonist U69,593 (0.01-0.1 mg/kg, s.c.) dose dependently prevented capsaicin (0.004 M)-induced allodynia in 38 and 42°C, and the largest U69,593 dose also reversed ongoing allodynia within this model. Two NMDA antagonists, ketamine and MK-801 (0.32-1.8 and 0.032-0.056 mg/kg, respectively), also prevented capsaicininduced allodynia in 38°C, but only variably in 42°C, at doses that did not cause robust thermal antinociceptive effects. At the largest doses studied, ketamine but not MK-801 also briefly reversed ongoing capsaicin-induced allodynia. The present model of topical capsaicin administration may be used to study antiallodynic effects of opioid and nonopioid compounds, as well as their ability to prevent and reverse allodynia, in unanesthetized nonhuman primates in the absence of tissue disruption.

The present studies show that serum prolactin levels are a highly sensitive, quantitative endpoint to study the potency and effectiveness of systemically administered E-2078, and show that the dynorphins may be potent and effective in causing some, but not all, the effects that are observed after the administration of synthetic kappa-agonists.

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