Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord

Stone, Laura S.; Vulchanova, Lucy; Riedl, Maureen; Wang, J.; Williams, Frank G.; Wilcox, George L.; Elde, Robert

doi:10.1016/s0306-4522(99)00209-2

Cited by 94 publications

(77 citation statements)

References 55 publications

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“…Previous studies suggested that the a 2A subtype mediates the antinociceptive eect of a 2 AR agonists in acute models of pain (Hunter et al, 1997;Lakhlani et al, 1997;Stone et al, 1997). However, because a 2 AR expression may be altered after nerve injury (Cho et al, 1997;Fareed et al, 1997;Birder & Perl, 1999;Stone et al, 1999;Shi et al, 2000), it is possible that the action of dexmedetomidine is altered by nerve injury or that the a 2 AR receptor subtype that is responsible for its antinociceptive eect is dierent.…”

Section: Introductionmentioning

confidence: 70%

“…However, the direction of the change is unclear. One report indicated that a 2A AR immunoreactivity was upregulated in DRG neurons after sciatic nerve injury (Birder & Perl, 1999), but another study found evidence for downregulation in the spinal dorsal horn after nerve injury (Stone et al, 1999). Moreover, while two studies showed that mRNA for a 2A AR was reduced after spinal nerve injury (Fareed et al, 1997;Cho et al, 1997), a recent study demonstrated an increase of this subtype in DRG neurons after nerve transection (Shi et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The observation that dexmedetomidine was active on the injured side at a dose that did not aect the contralateral limb, further suggests that the injury induces adrenergic sensitivity. This may occur at the level of the ipsilateral dorsal root ganglia (DRG) and/or the spinal dorsal horn, where changes in a 2 AR expression have been described (Cho et al, 1997;Fareed et al, 1997;Birder & Perl, 1999;Stone et al, 1999;Shi et al, 2000). However, the direction of the change is unclear.…”

Section: Discussionmentioning

confidence: 99%

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Contribution of α₂ receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Malmberg¹,

Hedley²,

Jasper³

et al. 2001

British J Pharmacology

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1 There is evidence that noradrenaline contributes to the development and maintenance of neuropathic pain produced by trauma to a peripheral nerve. It is, however, unclear which subtype(s) of a adrenergic receptors (AR) may be involved. In addition to pro-nociceptive actions of AR stimulation, a 2 AR agonists produce antinociceptive eects. 2 Here we studied the contribution of the a 2 AR subtypes, a 2A , a 2B and a 2C to the development of neuropathic pain. We also examined the antinociceptive eect produced by the a 2 AR agonist dexmedetomidine in nerve-injured mice. 3 The studies were performed in mice that carry either a point (a 2A ) or a null (a 2B and a 2C ) mutation in the gene encoding the a 2 AR. To induce a neuropathic pain condition, we partially ligated the sciatic nerve and measured changes in thermal and mechanical sensitivity. 4 Baseline mechanical and thermal withdrawal thresholds were similar in all mutant and wild-type mice; and, after peripheral nerve injury, all mice developed comparable hypersensitivity (allodynia) to thermal and mechanical stimulation. 5 Dexmedetomidine reversed the allodynia at a low dose (3 mg kg 71 , s.c.) and produced antinociceptive eects at higher doses (10 ± 30 mg kg 71) in all groups except in a 2A AR mutant mice. The eect of dexmedetomidine was reversed by intrathecal, but not systemic, injection of the a 2 AR antagonist RS 42206. 6 These results suggest that neither a 2A , a 2B nor a 2C AR is required for the development of neuropathic pain after peripheral nerve injury, however, the spinal a 2A AR is essential for the antinociceptive eects of dexmedetomidine.

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Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Contribution of α₂ receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Malmberg¹,

Hedley²,

Jasper³

et al. 2001

British J Pharmacology

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“…Cannabinoid receptors are found in the substantia gelatinosa of the spinal cord, suggesting modulation of nociceptive input from primary afferent neurones, and both cannabinoid receptors and a 2 -adrenoceptors are found in the peripheral nervous system on primary afferent neurones (Khan et al, 1999;Pertwee, 2001;Howlett et al, 2002). However, some studies suggest that the antinociceptive actions of a 2 -adrenoceptors are purely mediated at the spinal level, mainly via the a 2A -subtype present in the substantia gelatinosa (Jones et al, 1982;Takano & Yaksh, 1992;Hamalainen & Pertovaara, 1995;Stone et al, 1998;Khan et al, 1999;Kamibayashi & Maze, 2000;Malmberg et al, 2001). Stimulation of a 2 -adrenoceptors in the spinal cord causes inhibition of afferent nociceptive impulses from Ad and C fibres, as well as modulation of substance P and calcitonin gene-related peptide release in the dorsal horn (Yaksh, 1985;Takano et al, 1993;Furst, 1999;Khan et al, 1999).…”

Section: Sm Tham Et Almentioning

confidence: 99%

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice

Tham

Angus

Tudor

et al. 2005

British J Pharmacology

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1 Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2 The interactions between the cannabinoid agonist CP55,940, a 2 -adrenoceptor agonist dexmedetomidine and m-opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (551C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed-ratio combinations of agonists (s.c.) in 1 : 1, 3 : 1 and 1 : 3 ratios of their respective ED 50 fractions. 3 CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. In the hot plate and tail flick assays, ED 50 values (mg kg À1 ) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays. 4 Thus, an a 2 -adrenoceptor agonist or m opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and m opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptorspecific agonists may allow an improved therapeutic separation from unwanted side effects.

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“…As in the rest of the CNS, the á 2A receptor is the predominant type in the cord (69,104,109) and appears to be responsible for analgesic actions of á 2 -receptor agonists per se and for their well known synergistic interactions with opioid µ receptor agonists (105). Evidence that tonic adrenergic control of rabbit cord is also directed at dorsal horn neurons arises from the fact that RX 821002 inhibits the spinal inhibitory effects of the ì-opioid fentanyl given by either i.v.…”

Section: Spinal Cord Functionmentioning

confidence: 99%

RX 821002 as a Tool for Physiological Investigation of α₂‐Adrenoceptors

Clarke

Harris

2002

CNS Drug Reviews

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RX 821002 is the 2-methoxy congener of idazoxan. In binding and tissue studies it behaves as a selective antagonist of á 2 -adrenoceptors, with at least 5 times greater affinity for these receptors than any other binding site. It does not select between the different types of á 2 -receptor. Although this drug probably has no future as a therapeutic agent, it remains a good probe for physiological activity at á 2 -adrenoceptors in animal experiments. A particularly useful feature of this compound is its lack of binding at I 1 and I 2 imidazoline receptors. However, it has relatively high affinity for 5-HT 1A receptors (at which it acts as an antagonist) and a tendency to behave as an inverse agonist at á 2A -adrenoceptors in some cell culture systems. These potential drawbacks may be overcome by careful design of experiments, and the greater selectivity of RX 821002 renders it much superior to yohimbine or idazoxan as a tool for probing physiological actions at á 2 -receptors. It can be compared favorably with other selective antagonists such as atipamezole.In physiological studies, RX 821002 augments norepinephrine release in the frontal cortex and increases drinking behavior in rat. In rabbit, intrathecal administration of this drug enhances somatic and autonomic motor outflows, showing that tonic adrenergic descending inhibition of withdrawal reflexes and sympathetic pre-ganglionic neurons is strong in this species. The potentiation of reflexes may be considered a pro-nociceptive action. In the same model, RX 821002 antagonizes the inhibitory effects of the ì opioid fentanyl, indicating that exogenous opioids synergize with endogenously released norepinephrine in the spinal cord. Thus, the careful use of RX 821002 has revealed several aspects of the physiological activity of á 2 -adrenoceptors in rabbit spinal cord and rat brain. We recommend that RX 821002 and/or compounds with similar selectivity for á 2 -adrenoceptors (atipamezole, MK-912, RS-79948) should be used in preference to yohimbine or idazoxan in all future studies of this type.

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Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord

Cited by 94 publications

References 55 publications

Contribution of α₂ receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Contribution of α₂ receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice

RX 821002 as a Tool for Physiological Investigation of α₂‐Adrenoceptors

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Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord

Cited by 94 publications

References 55 publications

Contribution of α2 receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Contribution of α2 receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2‐adrenoceptor agonists in acute pain models in mice

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

Contact Info

Product

Resources

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Contribution of α₂ receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Contribution of α₂ receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice

RX 821002 as a Tool for Physiological Investigation of α₂‐Adrenoceptors