Periaqueductal grey cyclooxygenase‐dependent facilitation of C‐nociceptive drive and encoding in dorsal horn neurons in the rat

Abstract

Key pointsA- and C-nociceptors make different contributions to pain. They signal fast and slow pain, respectively, and C-nociceptors drive central sensitisation.Cyclooxygenase-1 (COX-1)-dependent descending facilitation from the periaqueductal grey (PAG) affects C-nociceptor spinal reflexes, but leaves A-nociceptor reflexes largely untouched. We studied the responses of spinal wide dynamic-range dorsal horn neurons to A- and C-nociceptor stimulation before and after COX-1 inhibition in the PAG. Inhibition of COX-1 descending facilitation disrupted the neuronal encoding of C-nociceptor information, but left the encoding of A-nociceptor information untouched. Inhibition of COX-1-dependent descending facilitation increased the activation threshold of wide dynamic range neurons to both A- and C-nociceptor input. The COX-dependent descending system from the PAG can therefore control the amount of C-nociceptor information reaching the CNS (slow, burning, aching, debilitating pain) without affecting the protective A-nociceptor information (sharp, well-localised, protective pain). AbstractThe experience of pain is strongly affected by descending control systems originating in the brainstem ventrolateral periaqueductal grey (VL-PAG), which control the spinal processing of nociceptive information. A- and C-fibre nociceptors detect noxious stimulation, and have distinct and independent contributions to both the perception of pain quality (fast and slow pain, respectively) and the development of chronic pain. Evidence suggests a separation in the central processing of information arising from A- vs. C-nociceptors; for example, inhibition of the cyclooxygenase-1 (COX-1)–prostaglandin system within the VL-PAG alters spinal nociceptive reflexes evoked by C-nociceptor input in vivo via descending pathways, leaving A-nociceptor-evoked reflexes largely unaffected. As the spinal neuronal mechanisms underlying these different responses remain unknown, we determined the effect of inhibition of VL-PAG COX-1 on dorsal horn wide dynamic-range neurons evoked by C- vs. A-nociceptor activation. Inhibition of VL-PAG COX-1 in anaesthetised rats increased firing thresholds of lamina IV–V wide dynamic-range dorsal horn neurons in response to both A- and C-nociceptor stimulation. Importantly, wide dynamic-range dorsal horn neurons continued to faithfully encode A-nociceptive information, even after VL-PAG COX-1 inhibition, whereas the encoding of C-nociceptor information by wide dynamic-range spinal neurons was significantly disrupted. Dorsal horn neurons with stronger C-nociceptor input were affected by COX-1 inhibition to a greater extent than those with weak C-fibre input. These data show that the gain and contrast of C-nociceptive information processed in individual wide dynamic-range dorsal horn neurons is modulated by prostanergic descending control mechanisms in the VL-PAG.

Cortical Regulation of Nociception of the Trigeminal Nucleus Caudalis

“…After several rinses, the sections were incubated for 1 h, at room temperature, in biotinylated donkey anti-goat (1:1000; Vector Labs, BA-5000). After additional rinses, sections were incubated in avidin-biotin-HRP conjugate (ABC, Vector Labs) (Hsu et al, 1981) for 30 min, followed by nickel-enhanced DAB (Adams, 1981). This resulted in a dark black reaction product (Fig.…”

Impairment of adenylyl cyclase‐mediated glutamatergic synaptic plasticity in the periaqueductal grey in a rat model of neuropathic pain

“…; Leith et al . ). The PAG has been implicated in the pathogenesis of several pain states, including neuropathic pain (Ho et al .…”

“…In addition to the ACC, the midbrain periaqueductal grey (PAG) is also an important supraspinal pain-regulating centre. It serves as a final common relay for descending pain inhibition by sending projections to the rostroventral medulla, which sends inhibitory outputs to the spinal dorsal horn (Heinricher et al 2009;Leith et al 2014). The PAG has been implicated in the pathogenesis of several pain states, including neuropathic pain (Ho et al 2013) and inflammatory pain (Drake et al 2014).…”

The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

“…Noxious withdrawal responses to A- and C-nociceptor selective stimulation were carried out as previously described (Leith et al, 2014, Leith et al, 2007, McMullan et al, 2004), by measurement of electromyographic activity in biceps femoris. Animals were anesthetized using isoflurane induction (4% in oxygen), and the external jugular vein and trachea were cannulated to allow maintenance of airway and anesthesia.…”

“…Animals were maintained at a depth of anesthesia where a weak withdrawal to noxious pinch could be elicited for the duration of the experiment. A- and C-cutaneous nociceptors were preferentially activated to elicit withdrawal reflex EMGs using a well-characterized contact heating protocol (Leith et al, 2014, Leith et al, 2007, McMullan et al, 2004). Two different rates of heating (2.5 °C/s and 7.5 °C/s) were applied to the dorsal surface of the left hind paw as these are known to preferentially activate slow/C-nociceptors (2.5 °C·s − 1 ) and fast/A nociceptors (7.5 °C·s − 1 ) respectively.…”