Peripheral Nerve Injury–Induced Changes in Spinal α2-Adrenoceptor–Mediated Modulation of Mechanically Evoked Dorsal Horn Neuronal Responses

Rahman, Wahida; D’Mello, Richard; Dickenson, Anthony H.

doi:10.1016/j.jpain.2007.11.010

Cited by 64 publications

(61 citation statements)

References 54 publications

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“…93 In spinal-nerve-ligated rats, the selective ␣ 2 -AR antagonist atipamezole failed to have an effect on spinal cord neuronal responses to peripheral stimuli, which suggests a downregulation of this endogenous inhibitory system in this pain model. 94 Given the increased behavioral responses of rats to mechanical stimuli after nerve injury, it is not surprising, but still intriguing, that the shift to this abnormal state seemingly occurs in the direction of increased spinal 5-HT 3 receptor-mediated facilitations that are matched by reduced ␣ 2 -AR-mediated inhibitory controls.…”

Section: Noradrenaline Function In Different Pain Statesmentioning

confidence: 99%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

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Summary:The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent ␣ 2 -adrenoceptor-mediated inhibitory system and 5-HT 3 (and likely also 5-HT 2 ) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control. Key Words: 5-HT receptors, 5-HT, serotonin, noradrenaline, RVM, rostral ventromedial medulla, opioidinduced hyperalgesia, neuropathy, fibromyalgia. PAIN, COMORBIDITIES, AND MONOAMINESPain and mood share certain neurological pathways in the CNS and have overlapping neurochemical bases, in particular their modulation by monoamine systems. This provides the substrate through which pain can influence mood, giving rise to comorbidities or secondary symptoms such as anxiety and depression, 1,2 and by the same continuum allows mood to exacerbate pain; indeed, patients with depression often present with symptoms that include medically unexplained pain, with the mean prevalence of such occurrence cited as 65%.1,3 Emotional facets of nociception play a significant role in the pain experience, with fear largely driving adaptive behaviors that enable avoidance of actual or impending harm. This therefore subserves the key function of pain, to protect the integrity and survival of an organism. Moreover, the role of emotions and state of mind in pain partly underlie the variable relationship between the intensity of damaging stimuli and perceived pain, such that at any given time and for any given nociceptive stimulus, painful response can be influenced by emotional state (the psychological context in which the stimulus is received), emotional trait (the psychological characteristics of the recipient), and cognitive set (attention and vigilance, for example).Depression is associated with abnormalities in the monoaminergic ...

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Section: Noradrenaline Function In Different Pain Statesmentioning

confidence: 99%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

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“…22,23,26,49 After peripheral nerve injury, changes within this descending NAergic control system have been implicated in the development of neuropathic pain. 19,25,39,46 Intriguingly, differences in the ability to engage this NAergic control system have been linked to the variable expression of neuropathic sensitisation in several nerve-injury models and across rat strains. 9,50 The descending NAergic system acts to delay the appearance of neuropathic signs in the acute phase after nerve injury but then fails to prevent the onset of sensitisation because of a progressive loss of spinal NAergic tone, 24 although it still acts to spatially limit the spread of sensitisation from the injured nerve territory.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone

Hughes

Hickey

Donaldson

et al. 2015

Pain

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The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal catheter implanted at the time of nerve injury for administration of reboxetine (10 mg) in both acute and chronic dosing experiments. In acute dosing experiments, both intrathecal and systemic (30 mg/kg) reboxetine partially reversed mechanical allodynia. This antiallodynic effect of intrathecal reboxetine was blocked by prior administration of yohimbine (a2-adrenoceptor antagonist, 30 mg) but not by prazosin (a1-adrenoceptor antagonist, 30 mg) or propranolol (b-adrenoceptor antagonist, 100 mg). Chronic intrathecal reboxetine (10 mg, intrathecally, twice daily for 2 weeks) suppressed the development of cold and mechanical allodynia. Nerve-injured animals demonstrated a place preference for intrathecal reboxetine, suggesting that it also reduced spontaneous pain. In contrast, an equivalent antiallodynic dose of systemic reboxetine (30 mg/kg) was aversive in both naive and TNT rats. On cessation of chronic intrathecal reboxetine, there was a gradual development of allodynic sensitisation that was indistinguishable from control TNT animals by 7 days after the end of dosing. Our results suggest that pharmacological restoration of spinal NAergic tone with intrathecal reboxetine can suppress both allodynia and spontaneous pain in the TNT model.

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“…Activation of these receptors may contribute to the efficacy of α-2 adrenergic receptor agonists and norepinephrine uptake inhibitors (e.g., tricyclic antidepressants) in some painful conditions (5)(6)(7)(8). Endogenous norepinephrine transmission does not affect baseline sensory thresholds, but its increased release during sustained pain is antinociceptive (9). Noradrenergic fibers in the spinal cord originate mainly in the pontine locus coeruleus (LC; A6) with some contributions from the brainstem A5 and A7 cell groups (10).…”

mentioning

confidence: 99%

Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues

Dimitrov

Kuo

Kohno

et al. 2013

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

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Nociceptive information is modulated by a large number of endogenous signaling agents that change over the course of recovery from injury. This plasticity makes understanding regulatory mechanisms involved in descending inhibition of pain scientifically and clinically important. Neurons that synthesize the neuropeptide TIP39 project to many areas that modulate nociceptive information. These areas are enriched in its receptor, the parathyroid hormone 2 receptor (PTH2R). We previously found that TIP39 affects several acute nociceptive responses, leading us to now investigate its potential role in chronic pain. Following nerve injury, both PTH2R and TIP39 knockout mice developed less tactile and thermal hypersensitivity than controls and returned to baseline sensory thresholds faster. Effects of hindpaw inflammatory injury were similarly decreased in knockout mice. Blockade of α-2 adrenergic receptors increased the tactile and thermal sensitivity of apparently recovered knockout mice, returning it to levels of neuropathic controls. Mice with locus coeruleus (LC) area injection of lentivirus encoding a secreted PTH2R antagonist had a rapid, α-2 reversible, apparent recovery from neuropathic injury similar to the knockout mice. Ablation of LC area glutamatergic neurons led to local PTH2R-ir loss, and barley lectin was transferred from local glutamatergic neurons to GABA interneurons that surround the LC. These results suggest that TIP39 signaling modulates sensory thresholds via effects on glutamatergic transmission to brainstem GABAergic interneurons that innervate noradrenergic neurons. TIP39's normal role may be to inhibit release of hypoalgesic amounts of norepinephrine during chronic pain. The neuropeptide may help maintain central sensitization, which could serve to enhance guarding behavior.supraspinal pain | allodynia | partial sciatic nerve ligation | Freund's adjuvant

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Peripheral Nerve Injury–Induced Changes in Spinal α2-Adrenoceptor–Mediated Modulation of Mechanically Evoked Dorsal Horn Neuronal Responses

Cited by 64 publications

References 54 publications

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone

Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues

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