Involvement of Opioid Receptors and α2-Adrenoceptors in Inhibitory Pain Modulation Processes: A Double-Blind Placebo-Controlled Crossover Study

Abstract

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.

Effect of combined opioid receptor and α2-adrenoceptor blockade on anxiety and electrically evoked startle responses

“…Experiment 1 (administration of yohimbine) (Vo and Drummond, 2016) and Experiment 2 (co-administration of naltrexone and yohimbine) (Vo et al, 2016) were carried out sequentially, approximately one year apart. Both experiments followed a randomised, double-blind, placebo-controlled crossover design (i.e.…”

“…The sample for Experiment 1 consisted of 13 males and 10 females aged between 18–52 years (Vo and Drummond, 2016), and the sample for Experiment 2 consisted of 16 females aged between 18–32 years (Vo et al, 2016). Exclusion criteria included pregnancy, breast-feeding, chronic pain, psychiatric disorders, medical treatment for a condition that affected the heart, blood vessels, skin, liver or kidneys, or a known sensitivity to yohimbine and/or naltrexone.…”

“…The procedures were the same in both experiments (Vo and Drummond, 2016; Vo et al, 2016), and are summarised below. On the day of the experiment, participants ate a normal breakfast and abstained from alcohol and caffeine.…”

“…Each session consisted of three stages (before drug administration, after drug administration, and after HFS), and lasted approximately three hours. In Stage 1, psychophysical tests were administered in the test and control arms, and on each side of the forehead, and blood pressure and heart rate were measured (findings reported elsewhere) (Vo and Drummond, 2016; Vo et al, 2016). Stage 2 began with the administration of drug(s) or placebo.…”

“…We recently investigated the effects of yohimbine alone (Vo and Drummond, 2016) and co-administration of yohimbine and the opioid antagonist naltrexone (Vo et al, 2016) on various indices of pain in healthy human participants. In these studies, high frequency electrical stimulation (HFS) triggered hypersensitivity at and around the stimulated site in the forearm but inhibited pain more broadly, particularly on the ipsilateral side.…”