Background In healthy humans, analgesia to blunt pressure develops in the ipsilateral forehead during various forms of limb pain. The aim of the current study was to determine whether this analgesic response is induced by ultraviolet B radiation (UVB), which evokes signs of peripheral sensitization, or by high‐frequency electrical stimulation (HFS), which triggers signs of central sensitization. Methods Before and after HFS and UVB conditioning, sensitivity to heat and to blunt and sharp stimuli was assessed at and adjacent to the treated site in the forearm. In addition, sensitivity to blunt pressure was measured bilaterally in the forehead. The effect of ipsilateral versus contralateral temple cooling on electrically evoked pain in the forearm was then examined, to determine whether HFS or UVB conditioning altered inhibitory pain modulation. Results UVB conditioning triggered signs of peripheral sensitization, whereas HFS conditioning triggered signs of central sensitization. Importantly, ipsilateral forehead analgesia developed after HFS but not UVB conditioning. In addition, decreases in electrically evoked pain at the HFS‐treated site were greater during ipsilateral than contralateral temple cooling, whereas decreases at the UVB‐treated site were similar during both procedures. Conclusions HFS conditioning induced signs of central sensitization in the forearm and analgesia both in the ipsilateral forehead and the HFS‐treated site. This ipsilateral analgesia was not due to peripheral sensitization or other non‐specific effects, as it failed to develop after UVB conditioning. Thus, the supra‐spinal mechanisms that evoke central sensitization might also trigger a hemilateral inhibitory pain modulation process. This inhibitory process could sharpen the boundaries of central sensitization or limit its spread.

Aims: Diabetic peripheral neuropathy (DPN) occurs in about half of people with diabetes, of whom a quarter may develop chronic pain. Pain may remain for years yet be difficult to treat because the underlying mechanisms remain unclear.There is consensus that processing excessive glucose leads to oxidative stress, interfering with normal metabolism. In this narrative review, we argue that oxidative stress may also contribute to pain. Methods: We reviewed literature in PubMed published between January 2005 and August 2021. Results and conclusions: In diabetes, hyperglycaemia and associated production of reactive species can directly increase pain signalling and activate sensory neurons; or the effects can be indirect, mediated by mitochondrial damage and enhanced inflammation. Furthermore, pain processing in the central nervous system is compromised in painful DPN. This is implicated in central sensitisation and dysfunctional pain modulation. However, central pain modulatory function is understudied in diabetes. Future research is required to clarify whether central sensitisation and/or disturbances in central pain modulation contribute to painful DPN. Positive results would facilitate early detection and future treatment.

Background High‐frequency electrical stimulation (HFS) of the human forearm evokes analgesia to blunt pressure in the ipsilateral forehead, consistent with descending ipsilateral inhibitory pain modulation. The aim of the current study was to further delineate pain modulation processes evoked by HFS by examining sensory changes in the arm and forehead; investigating the effects of HFS on nociceptive blink reflexes elicited by supraorbital electrical stimulation; and assessing effects of counter‐irritation (electrically evoked pain at the HFS‐conditioned site in the forearm) on nociceptive blink reflexes before and after HFS. Methods Before and after HFS conditioning, sensitivity to heat and to blunt and sharp stimuli was assessed at and adjacent to the conditioned site in the forearm and on each side of the forehead. Nociceptive blink reflexes were also assessed before and after HFS with and without counter‐irritation of the forearm. Results HFS triggered secondary hyperalgesia in the forearm (a sign of central sensitization) and analgesia to blunt pressure in the ipsilateral forehead. Under most conditions, both HFS conditioning and counter‐irritation of the forearm suppressed electrically evoked pain in the forehead, and the amplitude of the blink reflex to supraorbital stimuli decreased. Importantly, however, in the absence of forearm counter‐irritation, HFS conditioning facilitated ipsilateral blink reflex amplitude to supraorbital stimuli delivered ipsilateral to the HFS‐conditioned site. Conclusions These findings suggest that HFS concurrently triggers hemilateral inhibitory and facilitatory influences on nociceptive processing over and above more general effects of counter‐irritation. The inhibitory influence may help limit the spread of sensitization in central nociceptive pathways.

These findings imply involvement of α2-adrenoceptors both in ipsilateral antinociceptive and pronociceptive pain modulation processes. However, a mechanism not involving α2-adrenoceptors appears to mediate analgesia in the ipsilateral forehead after HFS.

Accepted ManuscriptInvolvement of opioid receptors and α 2 -adrenoceptors in inhibitory pain modulation processes: a double-blind placebo-controlled crossover study This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 2 AbstractIn healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only evokes local signs of central sensitization but also triggers broader ipsilateral inhibitory influences on pain akin to a lateralized form of conditioned pain modulation. Paradoxically, some of these inhibitory influences are augmented by α 2 -adrenoceptor blockade. To determine whether opioid peptides mediate inhibitory effects after HFS, the opioid receptor antagonist naltrexone was co-administered orally with the α 2 -adrenoceptor antagonist yohimbine in 16 healthy women in a double-blind placebo-controlled crossover study. In each session, mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, pain ratings to electrical stimulation of HFS-treated or control sites in the forearm were assessed during and after painful stimulation of each temple. Unlike yohimbine alone, the naltrexone + yohimbine combination blocked analgesia evoked by HFS in the ipsilateral forehead to blunt pressure, and opposed the ipsilateral inhibitory effect of pain in the temple on electrically-evoked pain at the HFS-treated site in the forearm. These findings imply involvement of opioid peptides in an ipsilateral analgesic response that complements the more generalized form of conditioned pain modulation. Opioid mediation of this ipsilateral analgesic response appears to override opposing α 2 -adrenoceptor effects.Perspective: HFS not only evokes local signs of central sensitization but also triggers a broader ipsilateral anti-nociceptive mechanism mediated by opioid receptors. Dysfunction of this lateralized pain modulation process might contribute to painful unilateral disorders such as migraine or complex regional pain syndrome.