Topical Capsaicin-Induced Allodynia in Unanesthetized Primates: Pharmacological Modulation

Butelman, Eduardo R.; Ball, Jonathan W.; Harris, Todd J.; Kreek, Mary Jeanne

doi:10.1124/jpet.103.052381

Cited by 29 publications

(36 citation statements)

References 30 publications

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“…Given the greater translational relevance of primate biology to humans, and in light of similarities between primate and human "challenge" pain models (Petersen and Rowbotham, 1999), we sought to examine the profile of KLYP961 in a capsaicin-induced thermal hyperalgesia model in rhesus nonhuman primates, a model that is sensitive to opioid and N-methyl-D-aspartate modulation (Butelman et al, 2003). The effects of MK-801 in the present study replicate earlier findings.…”

Section: Discussionsupporting

confidence: 67%

See 1 more Smart Citation

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Symons

Nguyen²,

Massari³

et al. 2010

J Pharmacol Exp Ther

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Nitric oxide (NO) derived from neuronal nitric-oxide synthase (nNOS) and inducible nitric-oxide synthase (iNOS) plays a key role in various pain and inflammatory states. KLYP961 (4-((2-cyclobutyl-1H-imidazo [4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one) inhibits the dimerization, and hence the enzymatic activity of human, primate, and murine iNOS and nNOS (IC 50 values 50-400 nM), with marked selectivity against endothelial nitric-oxide synthase (IC 50 Ͼ15,000 nM). It has ideal drug like-properties, including excellent rodent and primate pharmacokinetics coupled with a minimal offtarget activity profile. In mice, KLYP961 attenuated endotoxinevoked increases in plasma nitrates, a surrogate marker of iNOS activity in vivo, in a sustained manner (ED 50 1 mg/kg p.o.). KLYP961 attenuated pain behaviors in a mouse formalin model (ED 50 13 mg/kg p.o.), cold allodynia in the chronic constriction injury model (ED 50 25 mg/kg p.o.), or tactile allodynia in the spinal nerve ligation model (ED 50 30 mg/kg p.o.) with similar efficacy, but superior potency relative to gabapentin, pregabalin, or duloxetine. Unlike morphine, the antiallodynic activity of KLYP961 did not diminish upon repeated dosing. KLYP961 also attenuated carrageenin-induced edema and inflammatory hyperalgesia and writhing response elicited by phenylbenzoquinone with efficacy and potency similar to those of celecoxib. In contrast to gabapentin, KLYP961 did not impair motor coordination at doses as high as 1000 mg/kg p.o. KLYP961 also attenuated capsaicin-induced thermal allodynia in rhesus primates in a dose-related manner with a minimal effective dose (Յ10 mg/kg p.o.) and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states.

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Section: Discussionsupporting

confidence: 67%

“…The effects of KLYP961, gabapentin, and MK-801 on capsaicin-induced thermal hyperalgesia were examined in rhesus nonhuman primates based on the methodology developed by Butelman et al (2003).…”

Section: Primate Efficacy Studiesmentioning

confidence: 99%

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Symons

Nguyen²,

Massari³

et al. 2010

J Pharmacol Exp Ther

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“…1989; Butelman et al. 2003). However, prior to oxaliplatin or vehicle infusion, animals were able to keep their tails in 10°C for at least 20 sec.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Shidahara

Ogawa

Nakamura

et al. 2016

Pharmacology Res & Perspec

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Oxaliplatin is a first‐line treatment for colorectal cancer. However, shortly following treatment, cold‐evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin‐induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy‐induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water (“cold hypersensitivity”) was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin‐induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin‐treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin‐induced peripheral neuropathy.

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“…Allodynia was elicited by topical application of capsaicin as described previously (Butelman et al, 2003). After baseline tail-withdrawal latency determinations, the tail of each subject was degreased with an alcohol pad.…”

Section: Methodsmentioning

confidence: 99%

“…For drug self-administration studies, MMP2200 and morphine were filtered (MillexGV 0.22-m filter; Millipore Corporation, Billerica, MA) and delivered i.v. Capsaicin (Sigma-Aldrich, St. Louis, MO) was dissolved in a vehicle composed of 70% alcohol and 30% sterile water approximately 15 min before use, and it was delivered transdermally (topical patch) as described previously (Butelman et al, 2003). Specifically, the patch consisted of a 1-cm 2 piece of two-ply gauze affixed to adhesive backing (23-mm wide; Nexcare Bandages) and 12-cm long elastic tape (5-cm wide; Elastikon Tape) purchased from Henry Schein (Denver, PA).…”

mentioning

confidence: 99%

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Carmo

Polt²,

Bilsky³

et al. 2008

J Pharmacol Exp Ther

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H 2 N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-␤-D-lactose)-CONH 2 (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for and ␦ receptors. Glycosylation promoted brain penetration and production of centrally mediated behavioral effects in mice; however, it is unknown whether the magnitude of enhanced brain penetration is sufficient to permit central mediation of drug effects and production of synergistic /␦ antinociceptive interactions after systemic administration in primates. To address this issue, the present study compared the effects of MMP2200 and the -agonist morphine in four behavioral procedures in rhesus monkeys. In an assay of thermal nociception, morphine (1.0 -5.6 mg/kg) produced dose-dependent antinociception, whereas MMP2200 (10 -56 mg/kg) was ineffective. In an assay of capsaicin-induced thermal allodynia, both morphine (0.01-1.0 mg/kg) and MMP2200 (0.032-3.2 mg/kg) produced dose-dependent antiallodynic effects. MMP2200-induced antiallodynia was blocked by the moderately -selective antagonist naltrexone (0.01 mg/kg), the ␦-selective antagonist naltrindole (1.0 mg/kg), and the peripherally selective opioid antagonist quaternary naltrexone (0.32 mg/kg). In an assay of schedulecontrolled behavior, both morphine (0.01-1.0 mg/kg) and MMP2200 (10 -56 mg/kg) decreased response rates. Morphine effects were antagonized by naltrexone (0.001-0.01 mg/kg); however, the effects of MMP2200 were not antagonized by either naltrexone (0.01 mg/kg) or naltrindole (1.0 mg/kg). In an assay of drug self-administration, morphine (0.0032-0.32 mg/kg/injection) produced reinforcing effects, whereas MMP2200 (0.032-0.32 mg/kg/injection) did not. These results suggest that systemically administered MMP2200 acted as a peripheral, /␦-opioid agonist with limited distribution to the central nervous system in rhesus monkeys. These results also suggest the existence of species differences in the pharmacokinetics and brain penetration of glycopeptides.Opioids act at three main types of opioid receptor-the , ␦, and receptors-and most opioid analgesics function primarily as agonists at receptors (Gutstein and Akil, 2005). One strategy to improve the therapeutic usefulness of opioids has been to combine -receptor activation with pharmacological manipulation of other targets to produce a net increase in desirable versus undesirable effects. For example, simultaneous activation of -and ␦-opioid receptors may produce enhanced antinociception with fewer undesirable effects than selective activation of either or ␦ receptors alone in both rodents (Vaught and Takemori, 1979;Heyman et al., 1989;Adams et al., 1993) and nonhuman primates (Dykstra et al., 2002;Stevenson et al., 2003).The simultaneous activation of and ␦ receptors can be achieved either with a mixture of selective and ␦ opioids or with a single compound that has mixed activity at both and ␦ receptors. Endogenous opioid neurotransmitters such as Met-and Leu-enkephalin represent one class of opioid receptor ligands that produce relatively nonselective agonist effe...

show abstract

Topical Capsaicin-Induced Allodynia in Unanesthetized Primates: Pharmacological Modulation

Cited by 29 publications

References 30 publications

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

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