The formalin-induced expression of tachykinin peptide and neurokinin receptor messenger RNAs in rat sensory ganglia and spinal cord is modulated by opiate preadministration

doi:10.1016/0306-4522(94)00442-8

Neuroscience

Volume 64, Issue 3, February 1995, Pages 729-739

https://doi.org/10.1016/0306-4522(94)00442-8 Get rights and content

Abstract

Tachykinin peptides such as substance P and neurokinin B have been widely studied as mediators of pain transmission. The expression of neurokinin-1 and neurokinin-3 receptor messenger RNAs in the spinal cord is increased following intense nociception. The opiate ligands morphine and naltrexone alter behavioral responses to formalin-induced pain and alter evoked substance P release. This study investigated whether these opiates similarly alter the expression of substance P-, neurokinin B-, neurokinin-1 receptor- and neurokinin-3 receptor-encoding messenger RNAs in spinal systems following formalin-induced nociception. Expression levels of various messenger RNAs were quantitated using solution hybridization-nuclease protection assays. Six hours after hindpaw treatment, the levels of substance P-encoding preprotachykinin messenger RNA in the lumbar dorsal root ganglia and neurokinin B, neurokinin-1 receptor and neurokinin-3 receptor messenger RNAs in the lumbar dorsal horn were increased by approximately two-fold as compared to sham-treated controls. Pretreatment with naltrexone resulted in a further increase in the nociception-induced substance P messenger RNA expression in the dorsal root ganglia; preprotachykinin messenger RNA expression was not affected by morphine. Nociception-induced neurokinin-1 receptor messenger RNA expression in the dorsal horn was blocked by morphine, but was not affected by naltrexone. Both morphine and naltrexone blocked the formalin-induced increases in neurokinin B and neurokinin-3 receptor messenger RNA levels. Increased neurokinin B messenger RNA expression may reflect increased neurokinin B turnover in spinal interneurons activated by nociception. Neurokinin-3 receptor messenger RNA expression levels varied closely with, and thus may be regulated by, the levels of neurokinin B messenger RNA in the same regions.

The results of this study indicate that pretreatment with opiate ligands modulates the expression of tachykinin peptide and neurokinin receptor encoding mRNAs in spinal systems following a peripheral chemogenic inflammatory stimulus. Thus, endogenous opioid systems may be involved in activity-induced changes in the expression of spinal tachykinin peptides and neurokinin receptors.

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Acute or chronic stress can alter hippocampal structure, cause neuronal damage, and decrease hippocampal levels of the neurotrophin brain-derived neurotrophic factor (BDNF). The tachykinin substance P and its neurokinin-1 (NK-1) receptor may play a critical role in neuronal systems that process nociceptive stimuli; their importance in stress-activated systems has recently been demonstrated by the antidepressant-like actions of NK-1 receptor antagonists. However, the functional similarities between neurokinin receptors in the hippocampus and those in sensory systems are poorly understood, as is the significance of hippocampal NK-1 receptor in the context of chronic pain. Therefore, we investigated the effects of immobilization stress or inflammatory stimuli on NK-1 receptor and BDNF gene expression in the rat hippocampus. Rats received an acute or chronic immobilization stress, or an acute (formalin) or chronic (complete Freund’s adjuvant) inflammatory stimulus to the right hind paw. Subsequently hippocampal volume and specific gravity were measured and NK-1 receptor and BDNF mRNA levels quantified using ribonuclease protection assays. Results showed that either stress or pain down-regulates expression of both NK-1 receptor and BDNF genes in the hippocampus. Hippocampal volume was increased by either pain or stress; this may be due to edema (decreased specific gravity). Thus, BDNF and NK-1 receptor gene plasticity may reflect sensory activation or responses to neuronal injury. These data may provide useful markers of hippocampal activation during chronic pain, and suggest similarities in the mechanisms underlying chronic pain and depression.
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The tachykinin substance P (SP) is a neuropeptide that is expressed in some nociceptive primary sensory afferents and in discrete populations of spinal cord neurons. Expression of spinal SP and the preprotachykinin-A (PPT-A) gene that encodes SP exhibits plasticity in response to conditions such as peripheral inflammation but the mechanisms that regulate expression are poorly understood. We have developed a spinal cord organotypic culture system that is suitable for the analysis of PPT-A gene promoter activity following biolistic transfection of recombinant DNA constructs. Spinal cord organotypic slices showed good viability over a 7-day culture period. Immunostaining for phenotypic markers such as NeuN and β-III tubulin demonstrated preservation of neurons and their structure, although there was evidence of axotomy-induced down-regulation of NeuN in certain neuronal populations. Neurokinin-1 receptor (NK-1R) immunostaining in laminae I and III was similar to that seen in acute slices. Biolistic transfection was used to introduce DNA constructs into neurons of these organotypic cultures. Following transfection with a construct in which expression of enhanced green fluorescent protein (EGFP) is controlled by the PPT-A promoter, we showed that induction of neuronal activity by administration of a forskolin analogue/high K⁺ (10 μM/10 mM) for 24 h resulted in a fourfold increase in the number of EGFP-positive cells. Similarly, a twofold increase was obtained after treatment with the NK-1R-specific agonist [Sar⁹,Met (O₂)¹¹]-substance P (10 μM). These data demonstrate the usefulness of this model to study physiological and pharmacological factors relevant to nociceptive processing that can modulate PPT-A promoter activity.
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It is reported that the neuropathic injury induces retrograde structural and metabolic changes, including satellite Schwannn cells, and that these retrograde changes are likely to alter the structural integrity of the ganglion including, perhaps, the potency of the extracellular compartment [7,21]. Under peripheral inflammation, the properties of DRG neurons were changed included the cell excitability [8,22], neuronal signal transduction [10,13,32], and neurotransmitter expression [14,20] and release [11,33]. Furthermore, our previous observation demonstrated that the spontaneous firings were originated from the inflammatory site because the cutting of the innervated nerve blocked the spontaneous activity, indicating that inflammation induced the cell firing [30].
Primary afferent neurons in mammalian dorsal root ganglia (DRGs) normally function as independent sensory communication elements. However, it has recently been shown that most DRG neurons are transiently activated when axons of neighboring neurons of the same ganglion are stimulated repetitively and the cross-depolarization contributes to this mutual cross-excitation. Here, we reported the cross-inhibition of mechanoreceptive information in DRG under peripheral inflammatory condition. Intracellular recordings were made in vivo from A-type afferent neurons in cat L_6–7 DRGs. Among spontaneously firing neurons both from control (Con) and carrageenan (Carg) injected cats, some A-type afferent neurons showed to have two distinct receptive fields on the hindpaw. Mechanical stimulation of one receptive field increased the ongoing activities, while stimulation of the other receptive field led to a decrease of spontaneous firings of the same neuron. These two distinct receptive fields are termed excitatory receptive field (ERF) and inhibitory receptive field (IRF), respectively. Peripheral inflammation significantly increased the prevalence of Aβ and Aδ neurons with two distinct receptive fields (Aβ: Con, 1.34%, n=149; Carg, 6.59%, n=182; P<0.05; Aδ: Con, 0%, n=138, Carg, 3.9%, n=102, P<0.05). Most interestedly, ERF stimulation-induced enhancement of cell firings can be suppressed by IRF stimulation. Similarly, IRF stimulation-induced decrease of cell discharges can be reversed by ERF stimulation. This interaction was not affected by cutting the dorsal roots at the place close to the recorded DRG. Preapplication of naloxone and yohimbine did not block the interaction. Taken together with previous reports, this intraganglionic cross-talking appears to be mediated by collision of retrograde spread of action potentials, or/and at least in part, by an activity-dependent diffusible excitatory substance released from neuronal somata and/or adjacent axons, and detected by neighboring cell somata.
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Behavioral models have been widely used to measure the development and maintenance of nociception-evoked responses and hyperalgesia, but the pain-related behaviors of the mouse are not identical to those of the rat [20]. Prior studies in our laboratory have primarily focused on the function of the NK-1 receptor and the tachykinin peptide substance P in the rat during chronic inflammatory pain [7,10–15]. Substance P has been implicated as a mediator of nociceptive sensory information in the nervous system [15–17].
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The formalin-induced expression of tachykinin peptide and neurokinin receptor messenger RNAs in rat sensory ganglia and spinal cord is modulated by opiate preadministration

Abstract

Molec. Brain Res.

Pain

Analyt. Biochem.

Neuroscience

Neuroscience

Pain

Pain

Neuroscience

Brain Res.

J. biol. Chem.

Neuropharmacology

Brain Res.

Pain

Pain

Brain Res.

J. biol. Chem.

Brain Res.

Brain Res.

Meth. Enzym.

Life Sci.

Brain Res.

Life Sci.

Trends Neurosci.

Neuropharmacology

Pain

Pain

Eur. J. Pharmac.

Molec. Brain Res.

Brain Res.

Neurosci. Lett.

Neuropeptides

Brain Res.

Neurosci. Lett.

Brain Res.

J. biol. Chem.

Neuropharmacology