Peripheral nociceptive effects of α2-adrenergic receptor agonists in the rat

Khasar, Sachia G.; Green, Paul G.; Chou, Billy J.; Levine, Jon D.

doi:10.1016/0306-4522(94)00562-j

Cited by 121 publications

(79 citation statements)

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“…For example, most evidence used in support of the a 2B AR and a 2C AR subtypes in a 2 -mediated antinociception has been obtained in rats (Khasar et al, 1995;Gold et al, 1997). A further caveat is that such evidence has also primarily concentrated on an assessment of hyperalgesia and/or nociceptor sensitization following a chronic, in¯ammatory stimulus or nerve injury (c.f.…”

Section: Discussionmentioning

confidence: 99%

“…In situ hybridization and/or immunohistochemical studies have demonstrated the presence of either mRNA or protein, respectively, for the a 2B AR and a 2C AR and, to a more controversial extent, a 2A AR, in the rat DRG (Nicholas et al, 1993;Gold et al, 1997). Some functional studies support the molecular biology and implicate both a 2B AR and a 2C AR involvement in noradrenaline (NA)-mediated regulation of nociceptive activity within the primary a erent neurone (Khasar et al, 1995). Thus, a 2C ARs located on the peripheral terminals of the primary a erent neurones have been proposed to mediate the peripheral antinociceptive e ects of NA following tissue injury.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a 2C ARs located on the peripheral terminals of the primary a erent neurones have been proposed to mediate the peripheral antinociceptive e ects of NA following tissue injury. In contrast, the situation for the a 2B AR appears to be more complex; a 2B ARs located on the terminals of sympathetic postganglionic neurones (Khasar et al, 1995;Gold et al, 1997) have been suggested to mediate NA-induced peripheral hyperalgesia, associated with tissue/nerve injury (Levine et al, 1986;Taiwo et al, 1990;Sato & Perl, 1991), through the release of prostanoids that subsequently activate/ sensitize the peripheral terminals of the primary a erent neurone. Recent molecular biological evidence demonstrating the presence of the a 2B AR in the DRG has proposed that these receptors, which will ultimately be located on the central Dex was administered 60 min before the test and compared to both the vehicle group at that time point and the respective pre-dose data.…”

Section: Discussionmentioning

confidence: 99%

“…In animal models of either acute nociception or chronic nerve/tissue injury, there is evidence to support the involvement of the a 2A AR (Millan, 1992;Millan et al, 1994) and a 2C AR (Khasar et al, 1995) subtype in the antinociception produced by a 2 AR-agonists. In contrast, the a 2B AR (Khasar et al, 1995) has been primarily implicated in the peripheral hyperalgesic properties of noradrenaline released in response to tissue/nerve injury (Levine et al, 1986;Taiwo et al, 1990).…”

mentioning

confidence: 99%

“…In contrast, the a 2B AR (Khasar et al, 1995) has been primarily implicated in the peripheral hyperalgesic properties of noradrenaline released in response to tissue/nerve injury (Levine et al, 1986;Taiwo et al, 1990). A recent study showing mRNA expression for the a 2B AR in the dorsal root ganglion (DRG) has suggested that this subtype may also play a role in the spinal antinociceptive e ects of a 2 AR-agonists (Gold et al, 1997).…”

mentioning

confidence: 99%

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Assessment of the role of α₂‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Hunter¹,

Fontana²,

Hedley³

et al. 1997

British J Pharmacology

246

139

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1 The role of a 2 -adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the a 2 AR selective agonist dexmedetomidine (Dex) in mice devoid of individual a 2 AR subtypes through either a point (a 2A ) or null (a 2B /a 2C ) mutation (`knock-out').2 In a rodent model of acute thermal nociception, the mouse tail immersion test, Dex, in wild type (WT) control animals, produced a dose-dependent increase in the threshold for tail withdrawal from a 528C water bath with mean ED 50 values of 99.9+14.5 (a 2A ), 94.6+17.8 (a 2B ) and 116.0+17.1 (a 2C ) mg kg 71 , i.p. 3 In comparison to the WT controls, Dex (100 ± 1000 mg kg 71 , i.p.), was completely ine ective as an antinociceptive agent in the tail immersion test in the a 2A AR D79N mutant animals. Conversely, in the a 2B AR and a 2C AR knock-outs, Dex produced a dose-dependent antinociceptive e ect that was not signi®cantly di erent from that observed in WT controls, with ED 50 values of 85.9+15.0 (P40.05 vs WT control) and 226.0+62.7 (P40.05 vs WT control) mg kg 71 i.p., respectively. 4 Dex (10 ± 300 mg kg 71 , i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the a 2A , a 2B and a 2C AR WT control animals with ED 50 values of 30.1+9.0, 23.5+7.1 and 32.3+4.6 mg kg 71 , i.p., respectively. Again, Dex (100 ± 1000 mg kg 71 , i.p.) was ine ective at modulating motor behaviour in the a 2A AR D79N mutants. In the a 2B AR and a 2C AR knock-out mice, Dex produced a dose-dependent reduction in spontaneous locomotor activity with ED 50 values of 29.1+6.4 (P40.05 vs WT control) and 57.5+11.3 (P40.05 vs WT control) mg kg 71 , respectively. 5 Dex was also found to produce a dose-dependent reduction in body temperature in the a 2A , a 2B and a 2C AR WT control mice with ED 50 values of 60.6+11.0, 16.2+2.5 and 47.2+9.1 mg kg 71 , i.p., respectively. In the a 2A AR D79N mutants, Dex had no e ect on body temperature at a dose (100 mg kg 71 , i.p.) that produced a signi®cant reduction (76.2+0.58C; P50.01 vs vehicle) in temperature in WT controls. However, higher doses of Dex (300 and 1000 mg kg 71 , i.p) produced a small, but statistically signi®cant decrease in temperature corresponding to 71.7+0.48C and 72.4+0.38C (both P50.01 vs vehicle), respectively. In the a 2B AR and a 2C AR knock-out mice, Dex produced a dose-dependent reduction in body temperature with ED 50 values of 28.4+4.8 (P40.05 vs WT control) and 54.1+8.0 (P40.05 vs WT control) mg kg 71 , respectively. 6 In conclusion, the data are consistent with the a 2A AR being the predominant subtype involved in the mediation of the antinociceptive, sedative and hypothermic actions of Dex. This pro®le would appear to indicate that an a 2A AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Assessment of the role of α₂‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Hunter¹,

Fontana²,

Hedley³

et al. 1997

British J Pharmacology

246

139

View full text Add to dashboard Cite

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Adrenergic Receptors

Pertovaara¹

2009

Peripheral Receptor Targets for Analgesia

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Mu, Delta, and Kappa opioid receptor agonists induce peripheral antinociception by activation of endogenous noradrenergic system

Romero

Guzzo

Duarte

2012

J of Neuroscience Research

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Opioid receptor agonists induce noradrenaline release in the supraspinal, spinal, and peripheral sites. Endogenous noradrenaline release can induce an antinociceptive effect by activation of the α(2) adrenoceptor. This interaction between the opioid and the adrenergic systems could be the alternative mechanism by which opioid receptor agonists mediate peripheral antinociception. Therefore, the aim of the present study was to verify whether peripheral antinociception induced by the μ, δ, and κ opioid receptor agonists DAMGO, SNC80, and bremazocine, respectively, through the endogenous noradrenergic system. All drugs were administered locally into the right hind paw of male Wistar rats. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E(2). DAMGO, SNC80, or bremazocine elicited local dose-dependent peripheral antinociception. This peripheral effect was antagonized by the nonselective α(2) adrenoceptor antagonist yohimbine and by the selective α(2C) adrenoceptor antagonist rauwolscine but not by the selective antagonists for α(2A), α(2B), and α(2D) adrenoceptor subtypes (BRL 44 480, imiloxan, and RX 821002, respectively). The opioid-induced effect was antagonized by the nonselective α(1) adrenoceptor antagonist prazosin and by the nonselective β adrenoceptor antagonist propranolol. Guanethidine, a depletor of peripheral sympathomimetic amines, restored approximately 50-60% of the opioid-induced peripheral antinociception. Furthermore, acute injection of the noradrenaline reuptake inhibitor reboxetine intensified the antinociceptive effects of low-dose DAMGO, SNC80, or bremazocine. This study provides evidence that DAMGO, SNC80, or bremazocine induces peripheral antinociception by noradrenaline release and interaction with adrenoceptors.

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Peripheral nociceptive effects of α2-adrenergic receptor agonists in the rat

Cited by 121 publications

References 30 publications

Assessment of the role of α₂‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Assessment of the role of α₂‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Adrenergic Receptors

Mu, Delta, and Kappa opioid receptor agonists induce peripheral antinociception by activation of endogenous noradrenergic system

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Peripheral nociceptive effects of α2-adrenergic receptor agonists in the rat

Cited by 121 publications

References 30 publications

Assessment of the role of α2‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Assessment of the role of α2‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Adrenergic Receptors

Mu, Delta, and Kappa opioid receptor agonists induce peripheral antinociception by activation of endogenous noradrenergic system

Contact Info

Product

Resources

About

Assessment of the role of α₂‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

Assessment of the role of α₂‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice