Differential involvement of reactive oxygen species in a mouse model of capsaicin-induced secondary mechanical hyperalgesia and allodynia

Abstract

Intradermally injected capsaicin induces secondary mechanical hyperalgesia and allodynia outside the primary (i.e., capsaicin-injected) site. This secondary mechanical hypersensitivity is attributed to central sensitization in which reactive oxygen species (ROS) play a key role. We examined whether ROS would be differentially involved in secondary mechanical hyperalgesia and allodynia using a mouse intraplantar capsaicin injection model. In mice, capsaicin-induced secondary mechanical hyperalgesia outlasted its allodynia counterpart. Unlike the hyperalgesia, the allodynia was temporarily abolished by an anesthetic given at the capsaicin-injected site. The ROS scavenger phenyl-N-tert-butylnitrone slowed the development of both secondary mechanical hyperalgesia and allodynia when administered before intraplantar capsaicin injection, whereas it inhibited only the allodynia when administered after capsaicin had already induced secondary mechanical hyperalgesia and allodynia. Intrathecal injection of the ROS donor KO2 induced both mechanical hyperalgesia and allodynia with the former outlasting the latter. Metformin, an activator of redox-sensitive adenosine monophosphate-activated protein kinase, selectively inhibited capsaicin-induced secondary mechanical allodynia and intrathecal KO2-induced mechanical allodynia. These results suggest that ROS is required for rapid activation of central sensitization mechanisms for both secondary mechanical hyperalgesia and allodynia after intraplantar capsaicin injection. Once activated, the mechanism for the hyperalgesia is long-lasting without being critically dependent on ongoing afferent activities arising from the capsaicin-injected site and the continuous presence of ROS. On the contrary, the ongoing afferent activities, ROS presence and adenosine monophosphate-activated protein kinase inhibition are indispensable for the maintenance mechanism for capsaicin-induced secondary mechanical allodynia.

Postinjury stimulation triggers a transition to nociplastic pain in mice

“…This concentration of capsaicin is commonly used as a chemical injury for producing acute pain by directly activating nociceptors (primarily producing the pain of burning sensation) 46 and inducing both peripheral 2 and central sensitization. 9,26 Before developing a nociplastic pain animal model using a postinjury thermal stimulation to increase postinjury pain, we first characterized capsaicin-induced sensitization, focusing on sex differences in the magnitude of capsaicin-induced thermal and mechanical hypersensitivity. In our radiant heat test condition, males showed a longer latency to withdrawal at baseline and a steeper trajectory back to the baseline level after capsaicin injection (Fig.…”

Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice

“…A subset of C-fiber primary afferents, which mediate neurogenic inflammation, is the main source of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) 2 , 3 . In rodents, noxious stimuli such as capsaicin, a pungent agonist of the transient receptor potential vanilloid 1 (TRPV1) channel 4 , evoke the peripheral release of CGRP which induces arteriolar vasodilatation 2 and of SP which elicits plasma protein extravasation 5 , and produce sensory responses, which encompasses acute nociception and prolonged mechanical allodynia 6 . Capsaicin administration to the human skin elicits a similar pattern of responses, consisting of local cutaneous vasodilatation and focal and transient burning pain (min) associated with widespread, sustained mechanical hypersensitivity (hrs) 7 .…”

Gonadal hormone–dependent nociceptor sensitization maintains nociplastic pain state in female mice

“…Before beginning experiments, mice were acclimated to both experimenters and testing conditions as previously described. 16,22 The center of the hind paw (;4 mm proximal to the capsaicin injection site) was probed 10 times with a von Frey filament (0.98 mN, diameter 0.13 mm, 74 mN/mm 2 ) that evoked nocifensive withdrawal responses in naïve mice 0% to 20% of the time. Percentage withdrawal was recorded.…”