Spinal Processing of Noxious and Innocuous Cold Information: Differential Modulation by the Periaqueductal Gray

Abstract

In addition to cold being an important behavioral drive, altered cold sensation frequently accompanies pathological pain states. However, in contrast to peripheral mechanisms, central processing of cold sensory input has received relatively little attention. The present study characterized spinal responses to noxious and innocuous intensities of cold stimulation in vivo and established the extent to which they are modulated by descending control originating from the periaqueductal gray (PAG), a major determinant of acute and chronic pain. In lightly anesthetized rats, hindpaw cooling with ethyl chloride, but not acetone, was sufficiently noxious to evoke withdrawal reflexes, which were powerfully inhibited by ventrolateral (VL)-PAG stimulation. In a second series of experiments, subsets of spinal dorsal horn neurons were found to respond to innocuous and/or noxious cold. Descending control from the VL-PAG distinguished between activity in nociceptive versus non-nociceptive spinal circuits in that innocuous cold information transmitted by non-nociceptive class 1 and wide-dynamic-range class 2 neurons remained unaltered. In contrast, noxious cold information transmitted by class 2 neurons and all cold-evoked activity in nociceptive-specific class 3 neurons was significantly depressed. We therefore demonstrate that spinal responses to cold can be powerfully modulated by descending control systems originating in the PAG, and that this control selectively modulates transmission of noxious versus innocuous information. This has important implications for central processing of cold somatosensation and, given that chronic pain states are dependent on dynamic alterations in descending control, will help elucidate mechanisms underlying aberrant cold sensations that accompany pathological pain states.

Novel TRPM8 Antagonist Attenuates Cold Hypersensitivity after Peripheral Nerve Injury in Rats

“…Acetone and ethyl chloride were applied as evaporative cooling stimuli. From recordings of skin temperature, these solvents have been described previously to represent innocuous and noxious stimuli, respectively, because the latter induces a withdrawal reflex in normal animals (Leith et al, 2010). Compared with baseline, 100 mg/kg M8-An did not significantly reduce the number of action potentials evoked by innocuous or noxious cold stimulation (one-way RM ANOVA, P .…”

“…Disrupting the integrity of spinal circuits modifies gating of cold stimuli; ablation of calcitonin gene-related peptide a-positive primary afferents results in a loss of inhibition of cold-sensitive spinal neurons . Spinal neuronal responses to cold are also subject to dynamic supraspinal modulation via the periaqueductal gray and rostral ventromedial medulla, which may sustain abnormal behaviors under pathologic conditions (Rahman et al, 2006;Taylor et al, 2007;Leith et al, 2010). The role of NMDA receptors in mediating central sensitization is well established (Woolf and Thompson, 1991).…”

Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies

“…Experimental evidence 12 shows that, during the execution of cognitive tasks not involving pain (e.g., the However, it would be simplistic to consider that painful stimuli always capture attention. It 3 We use the term salience to refer to the physical properties of the stimulus that captures attention (bottom-up). We use relevance to refer to the characteristics of the stimulus that make it pertinent for cognitive goals (top-down).…”

A novel method for delivering ramped cooling reveals rat behaviours at innocuous and noxious temperatures: A comparative study of human psychophysics and rat behaviour

“…Such withdrawals occur at temperatures similar to those that evoke withdrawal in lightly anaesthetised animals which, by definition [32], are nociceptor driven [24,33] . This full withdrawal behaviour and the correlate in humans is therefore more likely to be driven by cold nociceptors, and may be an appropriate measure to use in preclinical cold evoked pain research.…”

“…Multiple afferent populations and ascending pathways inform perception and behavioural responses [23], and processing, particularly of noxious cold information, is also influenced by descending modulation from brainstem centres [24][25][26]. Further complexity is added to interpretation of findings by methodological differences between studies, including stimuli (magnitude; area; skin type) and outcomes (psychophysics, behaviour, neuronal properties, imaging).…”