Nerve growth factor induces P2X₃ expression in sensory neurons

Abstract

Glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) are neuroprotective for subpopulations of sensory neurons and thus are candidates for pain treatment. However, delivering these factors to damaged neurons will invariably result in undamaged systems also being treated, with possible consequences for sensory processing. In sensory neurons the purinergic receptor P2X 3 is found predominantly in GDNF-sensitive nociceptors. ATP signalling via the P2X 3 receptor may contribute to pathological pain, suggesting an important role for this receptor in regulating nociceptive function. We therefore investigated the effects of intrathecal GDNF or NGF on P2X 3 expression in adult rat spinal cord and dorsal root ganglia (DRG). In control spinal cords, P2X 3 expression was restricted to a narrow band of primary afferent terminals within inner lamina II (II i ). Glial cell line-derived neurotrophic factor treatment increased P2X 3 immunoreactivity within lamina II i but not elsewhere in the cord. Nerve growth factor treatment, however, induced novel P2X 3 expression, with intense immunoreactivity in axons projecting to lamina I and outer lamina II and to the ventromedial afferent bundle beneath the central canal. In the normal DRG, we found a greater proportion of P2X 3 -positive neurons at cervical levels, many of which were large-diameter and calcitonin gene-related peptide-positive. In both cervical and lumbar DRG, the number of P2X 3 -positive cells increased following GDNF or NGF treatment. De novo expression of P2X 3 in NGF-sensitive nociceptors may contribute to chronic in¯ammatory pain.

Cyclophosphamide-Induced Bladder Inflammation Sensitizes and Enhances P2X Receptor Function in Rat Bladder Sensory Neurons

“…Finally, the increase in peak current density was associated with an increase in the maximum current rather than a change in the EC 50 . Consistent with this interpretation, others have demonstrated an increase in P2X 3 receptor protein after inflammation of the hind limb footpad (Xu and Huang 2002), presumably due to up-regulation of P2X receptor transcripts by NGF (Ramer et al 2001), which is also increased after bladder inflammation (Lamb et al 2004;Vizzard 2000). We did not directly examine input resistance of bladder neurons following CYP treatment.…”

The roles of nerve growth factor and cholecystokinin in the enhancement of morphine analgesia in a rodent model of central nervous system inflammation

“…This may be explained by evidence from recent studies suggesting that NGF can directly influence opioid receptors in-vitro, in transgenic animals, or in inflammatory pain models (McDowell, 2004;Molliver et al, 2005;Mousa et al, 2007). Alternatively, numerous studies show that chronic systemic or intrathecal NGF administration results in multiple changes in neuropeptides involved in nociception (Malcangio et al, 1997;Malcangio et al, 2000;Jongsma Wallin et al, 2001;Ramer et al, 2001;Bowles et al, 2004) and potentially in morphine sensitivity. While we expect that 2 day intrathecal LPS treatment produce increases in spinal NGF, this hypothetical increase may not be the same as that induced by 7 day intrathecal infusion of βNGF.…”

Differences in Innervation and Innervated Neurons between Hip and Inguinal Skin

“…Nakajima (&), S. Ohtori, S. Yamamoto, K. Takahashi, Y. Harada Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan e-mail: g-naka@hotmail.co.jp the GDNF-neurons express the GDNF receptor [12,19,20]. NGF and GDNF in these neurons regulate the expression of various pain-related molecules, including substance P, calcitonin gene-related peptide (CGRP), the P2X 3 receptor, and vanilloid receptor 1, thereby regulating pain perception [14,15]. The two neuron types can be distinguished by immunoreactivity (IR) for CGRP or isolectin B4 (IB4) binding [20].…”