Projection Neurons in Lamina I of Rat Spinal Cord with the Neurokinin 1 Receptor Are Selectively Innervated by Substance P-Containing Afferents and Respond to Noxious Stimulation

Abstract

Lamina I of the spinal cord is densely innervated by nociceptive primary afferents, many of which contain substance P. It contains numerous projection neurons: the majority of these respond to noxious stimuli, however some are activated by cooling. In the rat, approximately 80% of the projection neurons express the neurokinin 1 (NK1) receptor, on which substance P acts, and most cells with this receptor are activated by noxious stimuli. Lamina I neurons can be classified morphologically into pyramidal, multipolar, and fusiform types. It has been reported in the cat that pyramidal neurons are activated only by cooling and that in monkey relatively few pyramidal cells are NK1 receptor-immunoreactive. We have used immunocytochemistry to examine the innervation of lamina I projection neurons in the rat by substance P-containing primary afferents and their responses to a noxious stimulus (subcutaneous formalin injection). NK1 receptor-immunoreactive projection cells received a significantly higher density of contacts from substance P-containing afferents than neurons that lacked the receptor. Most contacts on NK1 receptor-immunoreactive cells were associated with synapses. Formalin injection induced c-Fos in approximately 80% of projection neurons with the NK1 receptor and in 25-45% of those without it. More than 80% of pyramidal neurons expressed the receptor, and for both substance P innervation and c-Fos expression there were no significant differences among different morphological types of NK1 receptor-immunoreactive neuron. We conclude that presence or absence of the NK1 receptor is a better indicator of function than morphology for lamina I projection neurons in the rat.

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

“…In particular, many lamina I neurons with NK1Rs send axons to brain regions involved in pain processing, while receiving synapses from SP-containing primary afferents (Todd et al, 2002). Therefore, synapses between SP-containing primary afferents and NK1R-containing projection neurons appear to be crucial in determining the intensity of pain signals.…”

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

“…The present study examined the relationship of VGlut2, VGlut3 transporters and NKI receptors with fos-I nuclei as both glutamate and NKI receptors have been shown to regulate pelvic reflexes [64,69]. Glutamate is the major excitatory neurotransmitter and recent studies have documented the distribution of glutamate transporters in the lumbosacral cord [2,34,38,51,57,63].…”

“…However, as shown in figure 3, VGlut 2 and VGlut3 immunostaining was frequently found in close proximity to the fos-I nuclei in the dorsal horn and medial and lateral gray. The presence of overlapping NKI receptors and fos-immunoreactivity in the medial dorsal horn and DGC suggests a functional role of NKI receptors in the regulation of lumbosacral spinal inputs that make collateral projections to deeper layers of the dorsal horn and project to the brain, in addition to regulating nociception [12,61,62,64].…”

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

“…Among these neuromodulators, SP, the role of which is clearly established and well documented, is considered as a key neuropeptide mediating nociceptive message transmission from peripheral afferents to sensory neurons located in the SC dorsal horn (DH) (4)(5)(6). In particular, it has been shown that projection neurons in lamina I of rat DH expressing neurokinin 1 receptors (rNK1s) are selectively innervated by SP-containing afferents and respond to noxious stimulation (7). Direct structural-functional evidence for SP-mediated nociceptive transmission has also been provided in cats by multidisciplinary studies that combined various approaches, including intracellular recording from DH neurons in vivo, characterization of these neurons on the basis of their responses to peripheral noxious stimulation, cellular labeling by horseradish peroxidase, and electron microscopic identification of synaptic contacts (6)(7)(8)(9).…”

“…In particular, it has been shown that projection neurons in lamina I of rat DH expressing neurokinin 1 receptors (rNK1s) are selectively innervated by SP-containing afferents and respond to noxious stimulation (7). Direct structural-functional evidence for SP-mediated nociceptive transmission has also been provided in cats by multidisciplinary studies that combined various approaches, including intracellular recording from DH neurons in vivo, characterization of these neurons on the basis of their responses to peripheral noxious stimulation, cellular labeling by horseradish peroxidase, and electron microscopic identification of synaptic contacts (6)(7)(8)(9). Moreover, intrathecal injection of SP conjugated to the cytotoxin saporin selectively destroyed DH neurons bearing rNK1 and strongly reduced hyperalgesia after capsaicin treatment, indicating that spinal rNK1 neurons are important for the development of hyperalgesia (4,5).…”