Inhibition of morphine analgesia by lithium: role of peripheral and central opioid receptors

Abstract

Intraperitoneal (i.p.) administration of lithium chloride (LiCl) has two effects on pain sensation: (1) it induces a transient hyperalgesia that is reversed by intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of the opioid receptor antagonist naloxone or by peripheral administration of the quaternary compound naloxone methiodide [Behav. Neurosci. 114 (2000) 1183]; (2) it produces a long-lasting (24 h) reduction in morphine analgesia and does so in the absence of hyperalgesia [Behav. Brain Res. 142 (2003) 89]. We confirmed that rats administered with LiCl showed a reduction in analgesia when administered morphine 24 h later. We also found that morphine analgesia was restored if LiCl had been preceded by i.p. or i.c.v. administration of naloxone or by i.p. administration of naloxone methiodide. However, i.p. administration of naloxone methiodide prior to testing 24 h after an injection with LiCl did not restore morphine analgesia. Thus, activity at peripheral and central opioid receptors is necessary for the inhibition of morphine analgesia by LiCl, but peripheral opioid receptors are not critical for the expression of this inhibition.

Introduction

Following infection or poisoning rats display a characteristic set of behavioural, affective and cognitive changes that reflect activation of sickness [21], [24] or recuperative [4] motivational systems evolved to reduce activity, conserve energy and facilitate recovery. The responses to immune activation include adipsia, aphagia, increased slow wave sleep, decreased locomotor as well as social activity, anhedonia and learning deficits (see [27], [32] for reviews). These sickness behaviours are accompanied by activation of pain facilitatory mechanisms that increase basal pain sensitivity (hyperalgesia) and attenuate pain inhibitory mechanisms (anti-analgesia). Specifically, intraperitoneal (i.p.) injection with illness-inducing agents [e.g. lithium chloride (LiCl) or bacterial lipopolysaccharides (LPS)], or presentation of cues associated with LiCl induces hyperalgesia in rodents in the tail-flick and formalin tests, but not the hot-plate test of pain sensitivity [40], [71], and inhibits morphine analgesia in the tail flick and hot-plate tests [16], [23], [46], [47], [48]. Illness-induced anti-analgesia can be dissociated from hyperalgesia. For instance, morphine analgesia is reduced in situations where hyperalgesia is not apparent, such as 24 h after injection with LiCl or LPS, or in the hot plate test [23].

The predominant theory is that cytokines released from stimulated immune cells signal the central nervous system to induce the behavioural changes observed during illness. Illness-induced hyperalgesia requires the release of cytokines from stimulated immune cells in the periphery as: (1) illness-induced hyperalgesia is blocked by i.p. injection of either macrophage metabolic inhibitors or antagonists against the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α); and (2) hyperalgesia is induced by i.p. injection of IL-1 and TNF-α [33], [65], [68]. Lesion and infusion studies have identified a critical role for vagal terminations in the nucleus of the solitary tract (NTS), and the eventual activation of a pain facilitatory pathway. This descends from the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn where excitatory amino-acid (especially N-methyl-d-aspartate [NMDA]), neuropeptide (cholecystokinin [CCK] and substance P) and nitric oxide (NO) systems are recruited [65], [66], [67], [68], [69], [70]. Thus, these forms of hyperalgesia involve the activation of pain facilitatory mechanisms within the CNS via stimulation of immune cells and subdiaphragmatic vagal sensory afferents in the periphery.

In addition, the endogenous opioid system has a role in the responses to illness. Opioid peptides and their receptors have been identified in the immune system and these have important immunomodulatory functions [36]. LPS, LiCl and cytokines induce the expression and release of opioid peptides and receptors in neurons and glia within the CNS [6], [52], [53], [63], and activity at central opioid receptors has powerful immunomodulatory effects [42]. Furthermore, opioidergic mechanisms are critical for many physiological and behavioural effects of LiCl, LPS and cytokines [3], [8], [13], [19], [30], [31], [55], and acute or chronic administration of opioids induces nausea, affects feeding, drinking and sleeping patterns, and produces learning deficits and anhedonia [1], [50], [51].

It has recently been demonstrated that illness-induced hyperalgesia requires activity at opioid receptors. McNally et al. [38] reported that the opioid receptor antagonist naloxone blocked LiCl-induced hyperalgesia when administered centrally or peripherally (as naloxone methiodide, a quaternary form of naloxone that does not cross the blood–brain barrier). This involvement of opioid receptors in illness-induced hyperalgesia is consistent with previous evidence of activation of pain facilitatory mechanisms by opioids. Acute and chronic administration of opioids shifts the dose response curve of opioid analgesia to the right, that is, such administration induces tolerance to the pain inhibitory effects of opioids. Hyperalgesia is also a common long-term consequence of chronic and acute administration of opioids [7], [11], [28], [29], [45], [64], and cues associated with morphine administration both reduce morphine analgesia and induce hyperalgesia in the absence of morphine [39], [56]. Importantly, both opioid induced tolerance and hyperalgesia can be prevented by opioid receptor antagonists [10], [11].

The evidence described shows that activity at opioid receptors is not only involved in LiCl-induced hyperalgesia but also results in the activation of anti-analgesic mechanisms. Therefore, the current experiments examined whether blocking opioid receptors will prevent and/or reverse LiCl-induced anti-analgesia. Prior work has established that a single injection of LiCl reduces morphine analgesia in the tail flick test for up to 24 h in the absence of hyperalgesia [23], [48]. Given the role of both central and peripheral opioid receptors in illness-induced hyperalgesia, we studied the effect of preceding injection of LiCl with naloxone administered systemically or restricted to the brain or the periphery. We also examined whether activity at peripheral opioid receptors was important for the expression of LiCl-induced morphine tolerance. Naloxone methiodide, which does not affect morphine analgesia at the doses used here [41], was administered before testing to examine if it reversed the effects of LiCl on morphine analgesia.