Sustained Morphine-Induced Sensitization and Loss of Diffuse Noxious Inhibitory Controls in Dura-Sensitive Medullary Dorsal Horn Neurons

Abstract

Overuse of medications used to treat migraine headache can produce a chronic daily headache, termed medication overuse headache (MOH). Although “overuse” of opioids, triptans, and over-the-counter analgesics can all produce MOH, the neuronal mechanisms remain unknown. Headache pain is likely to be produced by stimulation of primary afferent neurons that innervate the intracranial vasculature and the resulting activation of medullary dorsal horn (MDH) neurons. The present study compared the receptive field properties of MDH dura sensitive neurons in rats treated with morphine to those given vehicle. Animals were implanted with osmotic mini-pumps or pellets for sustained subcutaneous administration of morphine or vehicle 6–7 days prior to recording from dura-sensitive neurons. Electrical and mechanical activation thresholds from the dura were significantly lower in chronic morphine treated animals when compared to vehicle controls. In addition, sustained morphine increased the cutaneous receptive field sizes. The presence of diffuse noxious inhibitory controls (DNIC) was examined by placing the tail in 55°C water during concomitant noxious thermal stimulation of the cutaneous receptive field, usually located in the ophthalmic region. The DNIC stimulus produced significant inhibition of heat-evoked activity in vehicle, but not chronic morphine treated animals. Inactivation of the rostral ventromedial medulla (RVM) with 4% lidocaine reinstated DNIC in chronic morphine treated animals. These results are consistent with studies demonstrating a loss of DNIC in patients that suffer from chronic daily headache and may partially explain why overuse of medication used to treat migraine can induce headaches.

Controversies in migraine treatment: opioids should be avoided

“…Moreover, in addition to the change in peripheral trigeminal afferents, animal studies demonstrate plasticity of central trigeminal neurons [29]. In morphine-treated rats, cutaneous receptive field sizes were larger, activation thresholds to electrical and mechanical stimulation of the dura were lower, and inhibition of heat-evoked activity by a remote noxious stimulus was abolished [30]. These results are consistent with an opioid-induced sensitization and a loss of Diffuse Noxious Inhibitory Controls (DNICs).…”

Central modulation of pain

“…Similarly, a more recent study using pain from an occlusion cuff and temporal summation from repeated pulses from a pressure algometer demonstrated deficiency in DNIC in CTT patients (143). In a recent study performed with rats, it was shown that persistent morphine exposure resulted in increased sensitivity to sensory thresholds and loss of DNIC in trigeminal neurons sensitive to dural stimulation (144). Here, it was hypothesized that loss of DNIC may contribute to development of medication-overuse headache (144).…”

“…In a recent study performed with rats, it was shown that persistent morphine exposure resulted in increased sensitivity to sensory thresholds and loss of DNIC in trigeminal neurons sensitive to dural stimulation (144). Here, it was hypothesized that loss of DNIC may contribute to development of medication-overuse headache (144). The DNIC paradigm has been used as a clinical tool to predict who might be at risk for enhanced postsurgical pain (145,146).…”

Descending pain modulation and chronification of pain

“…Additional studies showed that DNIC is integrated at the level of the dorsal reticular nucleus (DRt), which communicates with the PAG and RVM and projects to the spinal cord [120,121]. Loss of DNIC was produced by persistent morphine exposure in rats, resulting in increased sensitivity to sensory stimuli of trigeminal neurons sensitive to dural stimulation [122]. Importantly, DNIC was restored in these animals by inactivating the RVM with lidocaine [122].…”