Modulation of Muscle Pain Is Not Somatotopically Restricted: An Experimental Model Using Concurrent Hypertonic-Normal Saline Infusions in Humans

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)—ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)—50 μl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.

Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord

It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.

Regionally Diffuse Muscle Pain-Hypersensitivity in Humans During Acute Muscle Pain

BackgroundWe have previously shown that an intramuscular infusion of 5% hypertonic saline (HS) produces a painful response to normally innocuous stimuli applied to overlying and adjacent skin regions. In the current study, we explored whether a similar interaction could be observed between adjacent, contralateral and remote muscles. Indeed, widespread muscle pain-hypersensitivity is a hallmark of chronic pain conditions such as fibromyalgia.Methods5% HS was infused into the flexor carpi ulnaris (FCU) muscle to develop a stable baseline pain (n=30). In separate experiments, each of the three test locations (n=10 per site), the adjacent abductor digiti minimi (ADM), contralateral FCU and contralateral tibialis anterior (TA) (part 1-3, respectively), 50μL of 0.9% normal saline (NS) was infused (in triplicate) prior to, during and following HS-induced muscle pain.ResultsUnder control conditions (no background pain), the infusion of NS was imperceptible by all subjects. In the presence of HS-induced background pain (FCU), in part 1 the NS co-infusion into ADM increased overall pain by 17%. This was replicated in the contralateral FCU (part 2) with a 12% pain increase, and in the TA (part 3) with a 15% pain increase in response to the NS co-infusions. Notably, over 80% of subjects perceived the NS-induced increase in pain at the HS-infusion location (FCU) rather than the NS-infusion location (adjacent, contralateral and remote).ConclusionsIntramuscular infusion of HS results in pain-hypersensitivity to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.SignificanceThis work provides evidence for a regionally diffuse type of pain hypersensitivity, manifesting as a painful response to normally sub-perceptual stimulation in the context of acute experimentally induced muscle pain. This phenomenon may provide parallels to clinically relevant painful conditions and neuropathies.

Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

A myriad of counter-stimuli, including algogens and cooling, could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Optical or chemogenetic activation of GRPR neurons evokes itch behavior that is partly dependent on NK1R activation. Importantly, we show that noxious or cooling counter-stimuli inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which could evoke a mix of itch and pain sensations, could exert both excitatory and inhibitory effects on GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby counter-stimuli inhibit itch by suppressing the function of GRPR neurons.HighlightsActivation of GRPR neurons evokes itch and is dependent upon NK1R activationGRPR neurons receive both direct and indirect inputs from C/Aδ fibersCounter-stimuli inhibit GRPR neurons via GABAergic signalingIncreased excitability of GRPR neurons in chronic itch condition

Intense and sustained pain reduces cortical responses to auditory stimuli: implications for the interpretation of Heterotopic Noxious Conditioning Stimulation in humans

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (Heterotopic Noxious Conditioning Stimulation, HNCS). While this effect is thought to rely on a spino-bulbo-spinal mechanism in animals (Diffuse Noxious Inhibitory Controls, DNIC), the underlying neurophysiology in humans may further involve other pathways. In this study, we investigated the role of supraspinal mechanisms in HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the Cold Pressor Test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuliduringHNCS can be ascribed entirely to supraspinal mechanisms. High-density electroencephalography (EEG) was recorded during HNCS and auditory stimuli were administered in three blocks,before,during, andafterHNCS. Nociceptive Withdrawal Reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reducedduringHNCS. Moreover, the amplitude of the NWR was significantly diminishedduringHNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions to DNIC-like effects in humans is questionable. We conclude that the net effects of HCNS cannot be measured independently from attentional/cognitive influences.

Plasticity in somatic receptive fields after nerve injury

Devor and Wall, in a pioneering electrophysiological study, examined the change in somatic receptive fields in the dorsal horn of the spinal cord after nerve injury. Rather than the anticipated loss of an area of electrophysiological perception, the system demonstrated ‘plasticity’ whereby novel receptive fields, remote to the corresponding area of damage, were evident. The authors postulated that this neuroplasticity occurred via a hitherto undefined spinal mechanism, which lead to an explosion of interest and research to elucidate the mechanisms of central plasticity. In this truly landmark paper, the idea of the nervous system being an inherently ‘hard-wired’ structure was made redundant and the concept of neuroplasticity was given robust form.

Does Equi–Minimum Alveolar Concentration Value Ensure Equivalent Analgesic or Hypnotic Potency?

Background Minimum alveolar concentration (MAC) has traditionally been used to compare the potency of volatile anesthetics. However, as it reflects the spinal mechanism of immobility rather than the cerebral mechanism of analgesia and hypnosis, it is doubtful that equi-MAC connotes equivalent analgesic or hypnotic potency. The level of analgesia and hypnosis can be assessed using surgical pleth index and bispectral index (BIS) values, respectively. This study was designed to compare the surgical pleth index and BIS values produced by equi-MAC of desflurane and sevoflurane in patients undergoing single-agent volatile anesthesia. Methods Eighty-nine patients were randomly allocated to two groups receiving either desflurane (n = 44) or sevoflurane (n = 45). Anesthesia was only maintained with assigned volatile anesthetic of age-corrected 1.0 MAC. Surgical pleth index values as an analgesic estimate and BIS values as a hypnotic estimate were obtained under standard tetanic stimulation. Results Post-stimulation surgical pleth index values (mean ± SD), the primary outcome, were significantly lower for the desflurane group than those for the sevoflurane group (49 ± 10 vs. 64 ± 14, difference, 15 [95% CI, 10 to 20], P < 0.001). The desflurane group showed significantly lower poststimulation BIS values (median [interquartile range]) than the sevoflurane group (36 [31 to 41] vs. 41 [38 to 47], difference, 6 [95% CI, 2 to 9], P = 0.001). Conclusions During a steady-state of 1.0 MAC, desflurane and sevoflurane did not cause similar surgical pleth index and BIS values under the standardized nociceptive stimulus. These findings suggest that equi-MAC of desflurane and sevoflurane may not ensure equivalent analgesic or hypnotic potency.