High-Efficacy 5-Hydroxytryptamine 1A Receptor Activation Counteracts Opioid Hyperallodynia and Affective Conditioning

Abstract

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT) 1A receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo-and proalgesic actions, and offer initial evidence that high-efficacy 5-HT 1A receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioidresistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.Although opioids produce powerful pain relief, pain may become intractable as tolerance develops to opioid analgesia; it has been proposed that this is because opioids may, paradoxically, induce pain. Indeed, a concept of signal transduction in central pain-processing systems (Colpaert, 1996) specifies that any input to such systems causes not a single effect but two dual effects that are bidirectional, or opposite in sign. Thus, morphine eventually causes not only analgesia as a "first order" effect but also a "second order" hyperalgesia that outlasts opioid receptor activation for some time. Upon chronic opioid exposure, the second order pain, or sensitization to nociceptive input, grows and neutralizes the first order analgesia. Considerable evidence now indicates that tolerance to opioid analgesia results from opioid-induced pain ("opioid pain"; here used to refer to hyperalgesia, allodynia, and hyperallodynia; Colpaert, 1996;Mao, 2002;Ossipov et al., 2003).Opioid pain is comprehensive, encompassing both the "physiological" (e.g., nociceptive) and the more recently identified (Scholz and Woolf, 2002) "pathological" (e.g., neuropathic) types of pain. Indeed, opioids not only produce hyperalgesia (i.e., an enhanced response to nociceptive stimulation; Colpaert, 1996) but also neuropathic-like allodynia (i.e., pain behaviors in response to innocuous stimuli; Ossipov et al., 2003). In human, opioid pain occurs after the intraoperative ...

Morphine Deprivation Increases Self-Administration of the Fast- and Short-Acting μ-Opioid Receptor Agonist Remifentanil in the Rat

“…However, it is possible that although the hyperalgesia assay detected the presence or absence of morphine withdrawal, it may have lacked the sensitivity to distinguish subtle differences in withdrawal magnitude induced by withdrawal. Subtle increases in withdrawal severity not detected by changes in acetic acid-induced writhing may be hypothesized to enhance the negative-reinforcing properties remifentanil, resulting in increased remifentanil self-administration (Colpaert et al, 2006). Regardless of changes in withdrawal severity, the enhanced responding observed across the 20 sessions may be because of the acquisition ("learning") of the operant response in relation to the negative-reinforcing properties of the drug.…”

“…These findings may reflect the bidirectional first and second order effects of opioid signal transduction (e.g., Colpaert, 1996). The analgesia observed in the MD group reflects morphine's direct activation of the opioid receptor (the first order effect), whereas the hyperalgesia observed in the MW group demonstrates the second order effect that is of the opposite direction of the initial response after direct activation (Colpaert, 1996;Bruins Slot and Colpaert, 1999c;Bruins Slot et al, 2002;Colpaert et al, 2006).…”

“…The withdrawal syndrome that occurs upon termination of chronic drug taking and/or administration is reportedly aversive and is alleviated by further opiate administration. Although the reinforcing effects of opiates have been clearly established in the absence of observable dependence (for review, see Woods and Schuster, 1971), some have hypothesized that continued opioid abuse and development of opiate addiction is primarily because of the termination of the aversive withdrawal state (e.g., Solomon and Corbit, 1974;Koob and Le Moal, 2001;Colpaert et al, 2006). An alternative and conceptually appealing notion is to argue that withdrawal enhances the positive-reinforcing effects of -opioid agonists, with repeated exposure to opiate self-administration in the presence of the withdrawn state to be vital to the observable enhancement (Hutcheson et al, 2001).…”

Clarifying the roles of homeostasis and allostasis in physiological regulation.

“…Colpaert and colleagues (Colpaert, Deseure, Stinus, & Adriaensen, 2006) hypothesized that drug-opposite, sign-reversal states have motivational properties that encourage further drug administration. Ossipov and colleagues (Ossipov et al, 2004) proposed a vicious circle-of-addiction hypothesis where overactive effector responses shift the balance point of the regulated variable into an aversive sign-reversal state which motivates drug taking.…”

Opioid-induced hyperalgesia: fact or fiction?

“…Alterations within the brain, including the rostoventral medulla and an increase in descending facilitation may also play a role in opioid-induced hyperalgesia. [7][8][9][10][11][12][13] Interestingly, the same mechanisms have been identified in the development of tolerance suggesting that tolerance may result from a pain sensitization process more than from a decrease in the opioid effectiveness. This is however unlikely to be the whole story with tolerance.…”