Chronic Morphine Increases Fos‐Positive Neurons After Concurrent Cornea and Tail Stimulation

Abstract

Objective The aim of the present study was to examine the effect of chronic morphine exposure on diffuse noxious inhibitory controls in a large population of neurons throughout the medullary dorsal horn, as assessed using immunocytochemistry for c-Fos protein. Background Overuse of medications, including the opioids, to treat migraine headache can lead to progressively more frequent headaches. In addition, chronic daily headache sufferers and chronic opioid users both lack the inhibition of pain produced by noxious stimulation of a distal body region, often referred to as diffuse noxious inhibitory controls. Methods In urethane anesthetized rats, Fos-positive neurons were quantified in chronic morphine and vehicle treated animals following 52°C noxious thermal stimulation of the cornea with and without the application of a spatially remote noxious stimulus (placement of the tail in 55°C water). Results When compared to chronic morphine treated animals that did not receive the spatially remote noxious stimulus, chronic morphine treated animals given corneal stimulation along with the spatially remote noxious stimulus demonstrated a 163% increase (p<0.05) in the number of Fos-positive neurons in the superficial laminae of the medullary dorsal horn and a 682% increase (p<0.01) in deep laminae that was restricted to the side ipsilateral to the applied stimulus. In contrast, no significant difference was found in Fos-like immunoreactivity in vehicle treated animals given concurrent cornea and tail stimulation or only cornea stimulation in either superficial or deep laminae. Conclusions It is proposed that an increase in descending facilitation and subsequent loss of diffuse noxious inhibitory controls contributes to the development of medication overuse headache.

Progesterone Application to the Rat Forehead Produces Corneal Antinociception

“…The effect of progesterone on the central processing of corneal inputs was examined using c-Fos immunohistochemistry induced by mustard oil application to the cornea. Mustard oil application to the cornea has been used extensively to evoke c-Fos in the Vsp, and drugs used to treat pain also reduce the number of corneal mustard oil-evoked Fos-positive neurons 16,34,35. Fos-positive neurons are located in two primary regions within the Vsp after noxious corneal stimulation with mustard oil 16.…”

“…The caudal zone of Vsp processes nociceptive inputs in a manner similar to the spinal cord dorsal horn and has a primary role in corneal nociception. Quantification of protein for the immediate early gene c-fos has been used extensively as a marker for neuronal activity following corneal stimulation 16,18,34. In the caudal zone, the number of Fos-positive neurons correlates directly with the intensity of noxious stimulation 16.…”

“…Fos-positive neurons were quantified in two regions of the Vsp: the rostral zone, located at the transition between Vi and Vc, and the caudal zone, located at the transition between Vc and C1 16,34. In the rostral zone, located 0.0 to −0.5 mm from obex, Fos-positive neurons were counted in a total of five sections per animal, while in the caudal zone, located −3.0 to −4.5 mm from obex, a total of 9 sections per animal were counted.…”

Activation of dura-sensitive trigeminal neurons and increased c-Fos protein induced by morphine withdrawal in the rostral ventromedial medulla

“…Furthermore, morphine exposure produced an increase in the number of pain-facilitating on-cells recorded in the RVM (20). Descending inhibition is also reduced in morphine-treated animals, as measured by the expression of DNIC, a phenomenon in which nociceptive neurons are inhibited by noxious stimulation in a distal body region (17,26). This reduction in descending inhibition might be the consequence of an increase in RVM facilitation.…”

“…Single unit electrophysiology of dura-sensitive neurons allowed for a detailed assessment of ongoing and noxious heat-evoked activity during RVM withdrawal conditions (17,24,25). As a complementary approach, immunohistochemistry for c-Fos protein was used to provide an overall population analysis of activated neurons following RVM withdrawal, including those located in the spinal trigeminal nucleus and the subnucleus reticularis dorsalis (SRD) (26–29). The SRD, located in the brainstem just medial to the spinal trigeminal subnucleus interpolaris, receives input from the RVM and regulates diffuse noxious inhibitory controls (DNIC) through an inhibitory descending pathway (30–39).…”