Electrophysiological studies on rat dorsal root ganglion neurons after peripheral axotomy: Changes in responses to neuropeptides

Abstract

The effect of three peptides, galanin, sulfated cholecystokinin octapeptide, and neurotensin (NT), was studied on acutely extirpated rat dorsal root ganglia (DRGs) in vitro with intracellular recording techniques. Both normal and peripherally axotomized DRGs were analyzed, and recordings were made from C-type (small) and A-type (large) neurons. Galanin and sulfated cholecystokinin octapeptide, with one exception, had no effect on normal C-and A-type neurons but caused an inward current in both types of neurons after sciatic nerve cut. In normal rats, NT caused an outward current in C-type neurons and an inward current in A-type neurons. After sciatic nerve cut, NT only caused an inward current in both C-and A-type neurons. These results suggest that (i) normal DRG neurons express receptors on their soma for some but not all peptides studied, (ii) C-and A-type neurons can have different types of receptors, and (iii) peripheral nerve injury can change the receptor phenotype of both C-and A-type neurons and may have differential effects on these neuron types.Peripherally axotomized animals represent one model to study neuropathic pain (1). A damaged nerve can contribute actively to chronic pain by generating abnormal discharges and by amplifying and distorting naturally generated signals (2, 3), whereby the soma of dorsal root ganglion (DRG) neurons can become a site of abnormal impulse generation (4, 5).Peripherally, nerve injury also causes changes in peptide expression in DRG neurons. Thus, the synthesis of substance P (6) and calcitonin gene-related peptide (7, 8) is reduced, and that of vasoactive intestinal polypeptide (9), galanin (GAL) (10), and neuropeptide tyrosine (NPY) (11) is increased. Also, the expression of neuropeptide receptors such as cholecystokinin B-type (CCK B ) receptors (12) and NPY type 1 receptors (Y1-Rs) (13) is changed. To what extent, if at all, these changes in chemical phenotype are related to pain is not well understood, but a better insight into the chemical machinery in primary sensory neurons after peripheral axotomy may provide a better understanding of pain syndromes accompanying peripheral nerve injury and could lead to improved treatment strategies.Using electrophysiological techniques, the effects of peptides such as enkephalin (14) and GAL (15) have been studied on cultured DRG neurons. In the present study we administered three different peptides, GAL (16), sulfated CCK octapeptide (CCK-8S) (17), and neurotensin (NT) (18) onto rat DRG somata in vitro and monitored responses using intracellular recording techniques. Acutely extirpated DRGs from both normal rats and ganglia removed 5-7 days after peripheral axotomy were studied. We previously have reported results on the effect of NPY and NT on normal ganglia using the same intracellular recording technique (19). MATERIALS AND METHODSAnimals and in Vitro Preparation. In Sprague-Dawley rats (female, 100-200 g body weight; n ϭ 76), the sciatic nerve was transected bilaterally at mid-thigh level under deep anesthesia [s...

Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats

“…In muscle, depolarization of the resting potential underlies inexcitability in hyperkalemic periodic paralysis (28) and contributes to reduced excitability in the rat model of critical illness myopathy (CIM) (29,30). We impaled dorsal root axons to determine the average resting potential and found values in both control and septic rats that were similar to values reported previously for dorsal root neurons (31,32). The average resting potential in axons from septic rats was slightly more depolarized than in axons from untreated rats, but the difference was not statistically significant (-55.7 ± 1.0 mV in untreated vs. -52.6 ± 1.2 mV in septic, P = 0.08).…”

Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

“…It is also possible that the greater efficacy of JMV-431 is attributable to the fact that it exerts its effects through selective stimulation of NTS2 receptors, whereas NT acts jointly via NTS1 and NTS2. This interpretation would be coherent with the differential electrophysiological effects of NT on large (expressing NTS2) versus small (expressing both NTS1 and NTS2) DRG neurons (Zhang et al, 1995(Zhang et al, , 1996Xu et al, 1997;Kawarada et al, 2000). It would also conform to the bivalent antinociceptive effects of NT, facilitatory at low doses and inhibitory at high concentrations, observed after local injection of the drug in the rostroventral medulla (Smith et al, 1997; Urban and Gebhart, 1997; Urban et al, 1999;Gui et al, 2004).…”

“…Indeed, under voltage-clamp conditions, the effect of NT on small DRG cells is mainly inhibitory via an outward current, whereas on large DRG neurons it is mainly excitatory, evoking an inward current (Zhang et al, 1995(Zhang et al, , 1996Xu et al, 1997;Kawarada et al, 2000). After axotomy, the current elicited by NT on small DRG neurons is shifted from outward to inward (Xu et al, 1997), whereas NTS1, but not NTS2, receptors are downregulated in the same cells (Zhang et al, 1995). Therefore, it is tempting to speculate that NTS1 is responsible for the inhibitory effects of NT on small ganglion cells, whereas NTS2 mediates the excitatory effects of NT on both small and large DRG neurons.…”

Inhibition of Inflammatory Pain by Activating B-Type Natriuretic Peptide Signal Pathway in Nociceptive Sensory Neurons

“…These neuropeptides are also involved in the modulation of DRG neuron activity (X. Zhang et al, 1995;Xu et al, 1997). Importantly, the expression of both these neuropeptides and their receptors are strongly altered after peripheral nerve injury and/or inflammation (Ji et al, 1994(Ji et al, , 1995X.…”