Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects

Park, Karen M; Max, Mitchell B.; Robinovitz, Elaine; Gracely, Richard H.; Bennett, Gary J.

doi:10.1016/0304-3959(95)00029-r

Cited by 170 publications

(100 citation statements)

References 43 publications

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“…On the other hand, capsaicin-induced allodynia has significant value in studying pain mechanisms and pharmacologic interventions in humans (46,47). Given that capsaicin-sensitive nerve fibers are involved in a variety of pain conditions, the full effectiveness of BU08028 in inhibiting capsaicin-induced allodynia may indicate its clinically relevant analgesic efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…The minimum effective dose of BU08028 to produce full antinociception was 0.01 mg/kg. The duration of action produced by this dose was 30 h, and it subsided by 48 h. To determine the antihypersensitive efficacy of BU08028, we used a clinically relevant model, capsaicininduced allodynia, which has been widely applied to evaluate analgesics in humans (46,47). Systemic BU08028 attenuated capsaicin-induced thermal allodynia in 46°C water both dosedependently [F(3, 9) = 360.8; P < 0.05] and time-dependently [F(3, 9) = 42.2; P < 0.05] (Fig.…”

Section: Bu08028 Produces Potent and Long-lasting Antinociceptive Andmentioning

confidence: 99%

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

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various wellhoned behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10-to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abusefree opioid analgesics.N/OFQ peptide receptor | respiratory depression | reinforcing effects | physical dependence | mu opioid peptide receptor P ain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of potential targets as analgesics in the last decade, mu opioid peptide (MOP) receptor agonists remain the most widely used analgesics for pain management (1). Several side effects associated with MOP receptor agonists have severely limited the value of opioid analgesics, however (2). Owing to the abuse liability and the high mortality rate caused by respiratory arrest, opioid abuse not only has dire consequences, but also leads to mounting medical and economic burdens in our society (3-5). There is a clear, unmet need for safe analgesics without abuse liability in the global community.Buprenorphine, a partial MOP receptor agonist, is considered a safe analgesic because of its ceiling effect on respiratory depression (6, 7). Buprenorphine is commonly used in both human and veterinary medicine to treat various pain conditions, including cancer pain and neuropathic pain (7,8). However, buprenorphine is not devoid of reinforcing effects, the most devastating side effect...

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Section: Discussionmentioning

confidence: 99%

Section: Bu08028 Produces Potent and Long-lasting Antinociceptive Andmentioning

confidence: 99%

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

Ding

Czoty

Kiguchi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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“…In contrast, the duration of mechanical hyperalgesia seems to be longer, approximately 2 h (Gilchrist et al 1996). Capsaicin has been widely used in clinical studies for evaluating the antinociceptive efficacy of different analgesics (Park et al 1995;Eisenach et al 1997;Kinnman et al 1997). Given the evidence that capsaicin-sensitive nerve fibers are involved in a variety of nociceptive conditions (Barthó et al 1990;Kim et al 1995;Winter et al 1995;Abbadie and Basbaum 1998), it is valuable to develop capsaicin-induced pain models in animals for evaluating different compounds and clarifying the underlying mechanisms (Sakurada et al 1996;Sluka et al 1997;Ko et al 1998Ko et al ,1999.…”

Section: Discussionmentioning

confidence: 99%

“…Capsaicin, the pungent ingredient in hot chili peppers, has been used to evoke nociceptive responses for evaluating analgesics in primates including humans (Park et al 1995;Eisenach et al 1997;Kinnman et al 1997;Ko et al 1998). Exposure of nociceptor terminals such as Cfibers to capsaicin initially leads to excitation of the neuron and the subsequent perception of pain associated with local release of inflammatory pain mediators such as substance P and calcitonin gene-related peptide (CGRP) (Holzer 1991;Winter et al 1995;Caterina et al 1997;Kilo et al 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Many findings have supported the feasibility of pharmacological studies of capsaicin-induced pain to investigate different types of potential analgesics (Park et al 1995;Sakurada et al 1996;Eisenach et al 1997;Sluka 1997). Nevertheless, there was no rodent study exploring the possibility of peripheral antinociceptive actions in the capsaicininduced pain model.…”

Section: Introductionmentioning

confidence: 99%

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Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats

Tuchman

Johnson

et al. 2000

Psychopharmacology

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Rationale-By acting on peripheral opioid receptors, opioid agonists can attenuate nociceptive responses induced by a variety of agents.Objectives-This study was conducted to characterize capsaicin-induced thermal hyperalgesia in rats and to evaluate the hypothesis that local administration of either mu or kappa opioid agonists (fentanyl and U50, 488, respectively) can attenuate capsaicin-induced nociception.Methods-Capsaicin was administered s.c. in the tail of rats to evoke a nociceptive response, which was measured by the warm-water tail-withdrawal procedure. Either fentanyl or U50,488 was coadministered with capsaicin in the tail to evaluate local antinociceptive effects. In addition, the local antagonism study was performed to confirm the site of action of both opioid agonists.Results-Capsaicin (0.3-10 μg) dose dependently produced thermal hyperalgesia manifested as reduced tail-withdrawal latencies in 45°C water. Co-administration of either fentanyl (0.32-3.2 μg) or U50,488 (10-100 μg) with capsaicin (3 μg) attenuated capsaicin-induced hyperalgesia in a dosedependent manner. Furthermore, this local antinociception was antagonized by small doses (10-100 μg) of an opioid antagonist, quadazocine, applied s.c. in the tail. However, the locally effective doses of quadazocine, when applied s.c. in the back (i.e., around the scapular region), did not antagonize either fentanyl or U50,488.Conclusions-In this experimental pain model, activation of peripheral mu or kappa opioid receptors can attenuate capsaicin-induced thermal hyperalgesia in rats. It supports the notion that peripheral antinociception can be achieved by local administration of analgesics into the injured tissue without producing central side effects.

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Two N‐methyl‐D‐aspartate receptors in rat dorsal root ganglia with different subunit composition and localization

Marvizón

McRoberts

Ennes

et al. 2002

J of Comparative Neurology

118

104

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N-methyl-D-aspartate (NMDA) receptors in sensory afferents participate in chronic pain by mediating peripheral and central sensitization. We studied the presence of NMDA receptor subunits in different types of primary afferents. Western blots indicated that rat dorsal root ganglia (DRG) contain NR1, NR2B, NR2C, and NR2D but not NR2A. Real-time RT-PCR showed that NR2B and NR2D were expressed at higher levels than NR2A and NR2C in DRG. Immunofluorescence with an antibody that recognized NR1 and another that recognized NR2A and NR2B showed that NR1 and NR2B colocalized in 90% of DRG neurons, including most A-fibers (identified by the presence of neurofilament 200 kDa). In contrast, an antibody recognizing NR2C and NR2D labeled only neurofilament-negative DRG profiles. This antibody stained practically all DRG cells that contained calcitonin gene-related peptide and neurokinins and those that bound isolectin B4. The percentage of cells immunoreactive for NR1, NR2A/NR2B, and NR2C/NR2D were the same in the T9, T12, L4, and L6 DRG. The intracellular distribution of the NR2 subunits was strikingly different: Whereas NR2A/NR2B immunoreactivity was found in the Golgi apparatus and occasionally at the plasma membrane, NR2C/NR2D immunoreactivity was found in the cytoplasm but not in the Golgi. The NR1 subunit was present throughout the cytoplasm and was more intense in the Golgi. These findings indicate that DRG neurons have two different NMDA receptors, one containing the NR1, NR2D, and possibly the NR2C subunits, found only in C-fibers, and the diheteromer NR1/NR2B, present in the Golgi apparatus of both A- and C-fibers.

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Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects

Cited by 170 publications

References 43 publications

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

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

Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats

Two N‐methyl‐D‐aspartate receptors in rat dorsal root ganglia with different subunit composition and localization

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