The Effect of Subcutaneous Naloxone on Experimentally Induced Pain

Abstract

Telephone+61 8 9360 2415Fax +61 8 9360 6492Keywords: opioids; thermal hyperalgesia; peripheral opioid analgesia; cold pressor; pain tolerance; pain sensitivityRunning head: opioid analgesia and hyperalgesia -2 - ABSTRACTThe heat pain threshold was assessed in 32 healthy participants after a mild burn on the dorsal surface of each hand, after injection of an opioid antagonist (80 µg naloxone) or vehicle alone (0.2 mL saline) into the burnt skin of one hand, and after repeated painful immersion of this hand in cold water for up to 180 s. We hypothesized that sensitivity to heat would decrease at the burn-injured site after the immersions, due to local release of opioids into the burnt skin.Naloxone augmented cold-induced pain during the immersions in participants who tolerated the longest immersions, implying that release of endogenous opioids suppressed cold-pain.After the immersions, sensitivity to heat decreased at the burn-injured site in the immersed hand, but naloxone did not block this effect. Instead, naloxone altered sensitivity to heat in unburnt skin, implying that thermal hyperalgesia at sites of burn injury masked the modulatory effects of opioids. In particular, naloxone blocked a decrease in sensitivity to heat at an unburnt site on the contralateral hand of participants who tolerated the longest immersions, consistent with central or systemic opioid release. Naloxone reduced sensitivity to heat at unburnt sites in participants who tolerated medium-length immersions, suggesting that an increase in systemic or central opioid activity evoked thermal hyperalgesia in this group. In addition, in a small group of participants who tolerated only brief immersions, naloxone blocked decreases in sensitivity to heat at an unburnt site in the immersed hand.These findings suggest that repeated painful immersions trigger local opioid release in participants who tolerate only brief immersions, and elicit central or systemic opioid release in participants who tolerate longer immersions.Perspective: This article demonstrates that repeated immersion of the hand in painfully cold water increases opioid activity, and that the increase in opioid activity exerts multiple opposing effects on sensitivity to heat. Individual differences in the response to opioids might contribute to individual differences in pain tolerance.

Regulation of Spinal Dynorphin 1-17 Release by Endogenous Pituitary Adenylyl Cyclase-Activating Polypeptide in the Male Rat: Relevance of Excitation via Disinhibition

“…The demonstrated activation of spinal Dyn-ergic neurons by disinhibition suggests that they function as a high-gain antinociceptive system that is kept in reserve. Given numerous reports of the inability of opioid receptor blockade to lower nociceptive response thresholds and induce nociception (El-Sobky et al, 1976;Grevert and Goldstein, 1978;Robertson et al, 2008;Younger et al, 2009), it is widely accepted that endogenous opioid-ergic neurons are normally quiescent. The current study provides an expanded understanding of basal opioid-ergic activity.…”

Stress-evoked opioid release inhibits pain in major depressive disorder

“…In human research, µ-opioid receptor blockade antagonized stress-induced analgesia evoked by noxious electric shocks [47,48], immersion of a limb in ice-water [28,40], the perception of failure on a difficult cognitive task [2,3,20], a combat video shown to Vietnam veterans with post-traumatic stress disorder [38], and a first-time parachute jump [27]. Effects of µ-opioid receptor blockade on experimental pain are more variable [16,23,40], possibly because of individual differences in sensitivity to or release of opioid peptides. For example, naloxone augments shock-induced pain and cortical evoked potentials in pain-tolerant people, but inhibits pain and cortical evoked potentials in pain-sensitive people [10].…”

“…For example, naloxone augments shock-induced pain and cortical evoked potentials in pain-tolerant people, but inhibits pain and cortical evoked potentials in pain-sensitive people [10]. We recently reported that µ-opioid receptor blockade facilitated pain induced by repeated immersions of a hand in ice-water in pain-tolerant subjects, but had no effect on pain induced by the first, less stressful, immersion [40]. In the present study, naltrexone failed to augment pain induced by electric shocks or single ice-water immersions in the group as a whole.…”

Responsiveness of C Neurons in Rat Dorsal Root Ganglion to 5-Hydroxytryptamine-Induced Pruritic Stimuli In Vivo

“…Itch stimuli evoke scratching or biting, whereas noxious stimuli evoke a withdrawal reflex, flinching, or licking (Kuraishi et al 1995(Kuraishi et al , 2008Nojima et al 2004). Opioids, which are commonly used for alleviation of pain, elicit itching (Hales 1980;Jeon et al 2005;Maxwell et al 2005;Slappendel et al 2000); conversely, the opioid receptor antagonist naloxone enhances pain but inhibits the itch sensation (Metze et al 1999;Robertson et al 2008). …”

“…Histamine-sensitive polymodal C fibers are also responsive to mustard oil, which is known to activate TRPA1, and there is no significant difference in the discharge patterns caused by itching or burning stimuli (Handwerker et al 1991). A new subtype of C fibers that is insensitive to mechanical stimuli was reported to respond to itch stimuli (Schmelz et al 1997). However, these fibers also respond to algogens such as capsaicin or bradykinin (Schmelz et al 2003).…”