Topical and Peripherally Acting Analgesics

Sawynok, Jana

doi:10.1124/pr.55.1.1

Cited by 307 publications

(176 citation statements)

References 330 publications

(319 reference statements)

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“…Sites where this regulation of opioid action may occur include both the peripheral and central terminals of the nociceptive neuron. In the peripheral terminals, opioid inhibition of VGCC may decrease neuronal excitability and the release of algogenic substances such as substance P from nociceptor nerve endings, particularly during inflammation when opioid receptors are upregulated in the terminals (Sawynok, 2003). At central nociceptor terminals in the spinal dorsal horn, opioids inhibit nociceptive transmission by reducing calcium influx into the presynaptic terminal through VGCC, thereby decreasing excitatory neurotransmitter release (Jessell and Iverson, 1977;Macdonald and Nelson, 1978;Aimone and Yaksh, 1989;Ueda et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

McDowell

2004

Neuroscience

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Nerve growth factor (NGF) promotes the survival of embryonic sensory neurons and maintains the phenotypic characteristics of primary nociceptive neurons postnatally. NGF also contributes to nociceptor activation and hyperalgesia during inflammatory pain states. The purpose of this study was to determine whether NGF might have an additional pronociceptive action by interfering with opioid-mediated analgesia in primary nociceptive neurons. Sensory neurons were isolated from the dorsal root ganglia of weanling rats and kept in standard culture conditions either with or without exogenous NGF (50 ng/ml). Currents through voltage-gated calcium channels were recorded from individual neurons using the whole cell patch clamp technique with Ba 2+ as the charge carrier (I Ba ). The μ-opioid agonist fentanyl (1 μM) and the GABA B agonist baclofen (50 μM) were used to test G protein-dependent inhibition of I Ba . Fentanyl inhibited I Ba by an average of 38±4% in untreated cells vs. 25±2% in NGF-treated cells (P<0.01). NGF had no effect on I Ba current magnitude or kinetics. The NGF-induced attenuation of opioid action was observed as early as 4 h after exposure, but was not seen when NGF was applied by bath perfusion for up to 40 min, suggesting that the effect was not mediated by a rapid phosphorylation event. The effect of NGF was prevented by K-252a (100 nM), an inhibitor of TrkA autophosphorylation. Baclofen-induced inhibition of I Ba , on the other hand, was not affected by NGF treatment, suggesting that NGF modulation of opioid-mediated inhibition occurred upstream from the G protein. This was supported by the finding that GTP-γ-S, an agonist independent G protein activator, inhibited I Ba similarly in both untreated and NGF treated cells. The results show that NGF selectively attenuated opioid-mediated inhibition of I Ba via TrkA receptor activation, possibly by altering opioid receptor function. Keywords neurotrophins; DRG neurons; G proteins; patch clampNerve growth factor (NGF) is a neurotrophin required for the survival of most primary nociceptive neurons during embryonic development. A large number of nociceptive neurons remain sensitive to NGF postnatally, and in adult animals NGF plays a role in both physiological and pathological pain conditions. In the resting state, low levels of NGF are needed for the expression of nociceptor markers such as the neuropeptides substance P and calcitonin-gene-related peptide (CGRP; Molliver and Snider, 1997;Patel et al., 2000), and for nociceptive afferents to retain their ability to respond to noxious stimuli (Ritter et al., 1991;Lewin and Mendell, 1994;McMahon et al., 1995;Bennett et al., 1998 (Donnerer et al., 1992;Woolf et al., 1994;McMahon et al., 1995;Koltzenburg et al., 1999).NGF may sensitize nociceptors in several ways. NGF has been shown to upregulate the TRPV1 channel, one of the molecular transducers of noxious heat which is also activated by capsaicin, and to increase capsaicin-induced currents in nociceptors (Nicholas et al., 1999;Shu and Mendell, 2001;J...

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Section: Discussionmentioning

confidence: 99%

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

McDowell

2004

Neuroscience

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“…It is common that capsaicin cream is applied repeatedly in clinical practice, and there is a report suggesting that analgesic effect was observed by repeated application of capsaicin 24 . It was suggested in that report, that depletion of neuropeptide substance P and calcitonin gene-related peptide (CGRP) released from C-fibers caused the effect, but desensitization through VR1 is considered to be the main action mechanism of the analgesic effect in the recent reports [9][10][11][12]25,26 . In addition, there are reports suggesting that the analgesic effect occurs because the epidermal nerve fibers of the parts to which capsaicin was applied, degenerate from a morphologic point of view 15,16,27 .…”

Section: Discussionmentioning

confidence: 99%

Histopathological Changes of Streptozotocin-induced Painful Diabetes and Antihyperalgesic Effect of Capsaicin Cream in Rats

et al. 2008

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Abstract:To investigate the association between streptozotocin (STZ)-induced painful diabetic neuropathy and the antihyperalgesic effect of capsaicin cream in rats, we first examined the antihyperalgesic effect of capsaicin cream and subsequently performed peripheral neurohistochemical examinations of neuropathic rats. Mechanical hyperalgesia occurred 2 weeks after STZ injection and persisted for 8 weeks of testing. The neuropathy was alleviated by a single application of 0.1% capsaicin cream, but not by cream base. The hyperalgesia did not decrease when the capsaicin cream was applied to normal animals. On the other hand, for dorsal root ganglion (DRG) neurons and hind paw cutaneous nerves, the neurohistochemical examination showed no difference between STZ rats and control rats with capsaicin (vanilloid) receptor subtype 1 (VR1) and NF200 double immunohistochemical staining of DRG neurons, but an increase in A-fibers was seen in the hind paw cutaneous nerves of the STZ rats compared to the control rats. Neither STZ rats nor control rats were toxically affected by the single application of 0.1% capsaicin cream. These results suggest that a single application of capsaicin cream exerts an antihyperalgesic effect in rats with painful neuropathy and increases peripheral A-fibers. However, we could not clarify how VR1 was involved in the effect in rats with STZ painful diabetic neuropathy. (J Toxicol Pathol 2008; 21: 97-104)

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“…Analgesia after local (topical) opioid administration has been amply demonstrated in patients with various types of acute (e.g., orthopedic, dental, abdominal, urological, and eye surgery) and chronic pain (e.g., rheumatoid and osteoarthritis, oral mucositis, complex regional pain syndrome) (Azad et al, 2000;Dionne et al, 2001;Stein et al, 2003;Faktorovich and Basbaum, 2010). Several comprehensive reviews summarized these findings and mostly concluded that topically applied opioids have a potential to improve pain, albeit many clinical trials are small (Sawynok, 2003;Kopf et al, 2006;Bigliardi et al, 2009;LeBon et al, 2009).…”

Section: A Treatment Of Pain and Inflammationmentioning

confidence: 99%

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

2011

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Topical and Peripherally Acting Analgesics

Cited by 307 publications

References 330 publications

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

Histopathological Changes of Streptozotocin-induced Painful Diabetes and Antihyperalgesic Effect of Capsaicin Cream in Rats

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

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