Isolated nociceptors reveal multiple specializations for generating irregular ongoing activity associated with ongoing pain

Abstract

Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors, but rodent models of pain-related OA have concentrated on allodynia rather than ongoing pain, and on OA generated in non-nociceptive Aβ fibers rather than C-fiber nociceptors. Little is known about how ongoing pain or nociceptor OA is generated. To define neurophysiological alterations underlying nociceptor OA, we have used isolated dorsal root ganglion neurons that continue to generate OA after removal from animals displaying ongoing pain. We subclassify OA as either spontaneous activity generated solely by alterations intrinsic to the active neuron or as extrinsically driven OA. Both types of OA were implicated previously in nociceptors in vivo and after isolation following spinal cord injury, which produces chronic ongoing pain. Using novel automated algorithms to analyze irregular changes in membrane potential, we have found, in a distinctive, nonaccommodating type of probable nociceptor, induction by spinal cord injury of 3 alterations that promote OA: (1) prolonged depolarization of resting membrane potential, (2) a hyperpolarizing shift in the voltage threshold for action potential generation, and (3) an increase in the incidence of large depolarizing spontaneous fluctuations (DSFs). Can DSFs also be enhanced acutely to promote OA in neurons from uninjured animals? A low dose of serotonin failed to change resting membrane potential but lowered action potential threshold. When combined with artificial depolarization to model inflammation, serotonin also strongly potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA that may promote ongoing pain in chronic and acute conditions.

Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons

“…Three physiological maladaptations were noted in recent work on the mechanisms underlying spontaneous activity in a model of spinal cord injury neuropathic pain. These included the development of a more positive resting membrane potential; a more hyperpolarized action potential threshold; and the occurrence of depolarizing spontaneous fluctuations in membrane potential (Odem et al, 2018). We found two of these occurring in human neurons with spontaneous activity, a more hyperpolarized action potential threshold (Table 1) and depolarizing spontaneous fluctuations ( Fig.…”

Nociceptive Biology of Molluscs and Arthropods: Evolutionary Clues About Functions and Mechanisms Potentially Related to Pain

“…Aplysia nociceptors have central cell bodies and axonal diameters that, while not large compared to axons of truly giant neurons in Aplysia ( Rayport et al, 1983 ; Steffensen et al, 1995 ), are much larger than the small axons coming from the far more numerous afferent neurons of unknown function that possess peripheral cell bodies ( Xin et al, 1995 ). Relatively rapid conduction in Aplysia nociceptors and rapid adaptation are functionally consistent with rapid detection of the onset of threatening peripheral stimulation rather than provision of continuing information to the CNS about ongoing (e.g., inflammatory) noxious states, which in mammals is primarily provided by C-nociceptors ( Odem et al, 2018 ). It is not known whether any of the small-diameter afferents or other sensory neurons in Aplysia have functions equivalent to those of mammalian C-fiber nociceptors – especially, the non-accommodating activity continuously induced by persistent states of injury and/or inflammation.…”

“…Noxious stimuli are detected by sensory neurons called primary nociceptors, and their activation (nociception) evokes defensive responses ( Walters, 1994 ; Tobin and Bargmann, 2004 ; Smith and Lewin, 2009 ; Sneddon, 2015 ; Burrell, 2017 ). Because of the potency of nociceptors in driving both human pain and pain-like responses in animals (discussed in Odem et al, 2018 ), including selected molluscs and arthropods, and because enhanced function of nociceptors contributes substantially to various persistent pain states in mammals ( Gold and Gebhart, 2010 ; Walters, 2012 ), a major focus of this article is on primary nociceptors.…”

Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020

“…Tissues treated with activated PRP will be invaded by PGFs, cytokines, and other platelet lysosomes. More specifically, when the dense granules release their contents, an abundance of pain-modulating 5-HT will be discharged [ 135 ]. In C-PRP, the platelet concentration is 5 to 7-fold higher than in peripheral blood.…”