The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord

Dickenson, Anthony H.; Chapman, Victoria; Green, G.M.

doi:10.1016/s0306-3623(96)00359-x

Cited by 369 publications

(195 citation statements)

References 53 publications

Supporting

Mentioning

188

Contrasting

Unclassified

Order By: Relevance

“…3a). Previous results have suggested that spinal NMDA receptors are also involved in driving postcrush hyperalgesia (Dickenson et al, 1997), and indeed intrathecal (IT) delivery of a low dose of NMDA (0.3 g/10 l) results in significant thermal hyperalgesia (Fig. 3b), and this hyperalgesia was again reversed by COX-2 but not a COX-1 inhibitor or vehicle.…”

Section: Resultsmentioning

confidence: 81%

“…Thus, rats pretreated 10 min before injury via an intrathecal infusion of a COX-2 inhibitor did not develop significant tactile allodynia, whereas animals treated with the COX-1 inhibitor or vehicle showed development of significant allodynia. Previous results have suggested that spinal NMDA receptors are also involved in driving postcrush hyperalgesia (Dickenson et al, 1997), and using IT delivery of NMDA permitted direct assessment of the spinal pharmacology of facilitated processing without having to initiate an injury state that might be altered by a systemically delivered agent. Indeed, IT delivery of a low dose of NMDA results in significant thermal hyperalgesia, and again, this hyperalgesia was again reversed by COX-2 but not a COX-1 inhibitor or vehicle.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia

Ghilardi¹,

Svensson²,

Rogers³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

Inhibitors of the isozyme cyclooxygenase-2 (COX-2) represent an important advance in pain management, although where and when these inhibitors can exert their antihyperalgesic actions are not completely understood. Here we show that unlike many peripheral tissues in which COX-2 is only expressed in physiologically significant levels after tissue injury, in the normal rat lumbar spinal cord, the majority of neurons and radial glia constitutively express high levels of COX-2 protein. Immediately after peripheral tissue injury and before any measurable upregulation of COX-2 protein in peripheral tissue or spinal cord, inhibition of constitutively expressed spinal COX-2 reduced injury-induced activation of primary afferent neurons, activation of spinal neurons, and the mechanical and thermal hyperalgesia that normally occurs after peripheral tissue injury. The present data demonstrate that constitutively expressed spinal COX-2 plays an important role in the initial hyperalgesia that follows peripheral tissue injury. These results suggest that blocking constitutive spinal COX-2 before tissue injury may reduce the initial peripheral and central sensitization that occurs after tissue injury.

show abstract

Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia

Ghilardi¹,

Svensson²,

Rogers³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The superficial dorsal horn contains neurons which modulate afferent information through projections to local spinal laminae, other spinal segments and the brain [20,54,62]. The laminae I and II fos-I neurons labeled in the present study could be involved in nociception or regulation of muscle sensitivity and non noxious inputs [37].…”

Section: Discussionmentioning

confidence: 57%

“…A recent study indicated that VGlut2 (not VGlut1) axons, supplied the majority of glutamate innervation of the parasympathetic preganglionic neurons [38] and the present study describes the overlap of VGlut2 with fos-I nuclei in the region of the parasympathetic preganglionic neurons in the lateral gray. Modulation of excitatory drive via glutamate AMPA receptors may occur in the dorsal horn since VGlut2 particularly overlapped with fos-I nuclei in the superficial dorsal horn, where glutamate release is thought to act on AMPA receptors [20]. Both VGlut2 and VGlut3 transporters may mediate spinal reflex excitatory drive in the DGC as they were both found to be codistributed with fos-I neurons.…”

Section: Discussionmentioning

confidence: 99%

Spinal neurons activated in response to pudendal or pelvic nerve stimulation in female rats

Alexander

Marson

2008

Brain Research

View full text Add to dashboard Cite

The overlapping distribution of spinal neurons activated with either pudendal sensory nerve or pelvic nerve stimulation was examined in the female rat using c-fos immunohistochemistry. Pudendal sensory nerve stimulation resulted in a significant increase in fos-positive cells in the ipsilateral dorsal horn and bilaterally in the medial, lateral and intermediate gray of L5-S1. Pelvic nerve stimulation resulted in significant increases of c-fos immunoreactive nuclei in the ipsilateral dorsal horn, lateral and intermediate gray and bilaterally in the medial gray of L5-S1. Co-distribution of fos immunoreactive nuclei with the vesicular glutamate transporters (VGlut2 and VGlut3) and neurokinin I receptors were found in distinct regions of the dorsal horn, medial and lateral gray. Specific areas in the medial dorsal horn, dorsal gray commissure, laminae VI and X and dorsal lateral gray were activated after stimulation of the pudendal sensory and pelvic nerves, suggesting these areas contain spinal neurons that receive both somatomotor and visceral inputs and are part of the intraspinal circuit that regulates sexual and voiding function.

show abstract

“…Hyperexcitability of neurons as well as hyperalgesia are mediated by NMDA receptor activation and are suppressed by intrathecal (IT) administration of selective NMDA receptor antagonists (5)(6)(7)(8). Inflammatory stimuli can also elicit spinal cord excitatory amino acid release (9) and induce expression of early response genes like c-Fos in spinal cord neurons (10).…”

mentioning

confidence: 99%

Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant‐induced arthritis

Boyle

Moore

Yang

et al. 2002

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To examine the effect of spinal cord adenosine (Ado) receptor stimulation on rat adjuvantinduced arthritis (AIA).Methods. Long-term intrathecal (IT) catheters were implanted into rats to provide spinal access for drug delivery. Animals were immunized with complete Freund's adjuvant at the tail base. Eight days later and every other day thereafter until day 20, rats were treated IT with the selective Ado A1 receptor agonist cyclohexyladenosine (CHA) or vehicle. In some experiments, animals received an additional daily intraperitoneal injection of the nonselective Ado antagonist theophylline. Paw swelling was measured by water displacement plethysmometry. The effect of IT CHA on the activation of activator protein 1 (AP-1) was determined by electromobility shift assay. Spinal cord c-Fos expression was determined by immunohistochemistry.Results. Spinal CHA significantly inhibited inflammation in AIA, with a mean ؎ SEM 20.9 ؎ 16.9% increase in paw swelling in the IT CHA group compared with 81.3 ؎ 10.6% in the saline group. The antiinflammatory effect of CHA was mediated through Ado receptors since the effect was reversed by coadministration of systemic theophylline. In addition, radiographs showed significantly less bone and cartilage destruction in the CHA-treated animals. Synovial expression of AP-1, which is a key regulator of metalloproteinase expression, was lower in IT CHA-treated animals. C-Fos expression was localized to spinal laminae I-VI, with a modest decrease observed in the superficial laminae in IT CHA-treated rats.Conclusion. These data demonstrate that the spinal cord can regulate peripheral inflammation. Therapeutic strategies that target the central nervous system might be useful in arthritis.The central nervous system (CNS) receives input from sites of peripheral inflammation and can, in turn, modulate the inflammatory process. For instance, inhibition of non-N-methyl-D-aspartate (NMDA) glutamate receptors in the lumbar dorsal horn suppresses knee swelling in rats after intraarticular injection with carrageenan. We have shown that spinal cord A1 adenosine (Ado) receptor agonists inhibit neutrophil accumulation in the skin of rats after intradermal injection with proinflammatory agents (1). In contrast to the knee edema model (2), this effect on neutrophil trafficking into peripheral sites is mediated by Ado-induced suppression of spinal NMDA receptor activation. The action of spinal cord Ado on neutrophil homing is independent of primary afferent fiber substance P and sympathetic neurons, but requires intact peripheral nerve connection since dorsal rhizotomy ablates the antiinflammatory activity (1).Understanding of the neural pathways and molecular mechanisms that process nociceptive information and subsequently regulate inflammatory peripheral responses is still in its formative stage. However, it is known that the spinal cord releases the excitatory amino acids glutamate and aspartate following nociceptive stimuli received via afferent C-fiber activation (3). Spinal cord neuronal re...

show abstract

The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord

Cited by 369 publications

References 53 publications

Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia

Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia

Spinal neurons activated in response to pudendal or pelvic nerve stimulation in female rats

Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant‐induced arthritis

Contact Info

Product

Resources

About