Endogenous Opioid-mediated Analgesia Research Articles

Abstract # 3146 Increased pain sensitivity and decreased opioid analgesia in t cell-deficient mice and implications for sex differences

The processing of pain in the central nervous system is now known to have an important immune component, including T cells. T cells have been shown to release endogenous opioids, and although it is well known that opioids have effects on T cell populations, very little attention has been given to the converse: how T cells may affect opioid regulation. We find here that in addition to displaying significantly increased baseline pain sensitivity across various pain modalities, T cell deficient mice exhibit pronounced deficiencies in morphine inhibition of thermal or inflammatory pain. Nude mice are also deficient in endogenous opioid-mediated analgesia, exhibiting no stress-induced analgesia from restraint. The relevant T cell subpopulation appears to be CD4 + T cells, since adoptive transfer of them but not CD8 + cells into nude mice rescues both the pain and morphine analgesia phenotypes. As previously reported, we also observe a sex difference in CD-1 mice, with females requiring 2–3-fold more morphine than males to produce equal analgesia. Nude mice display no sex differences in morphine analgesia, and the sex difference is restored in nude mice of either sex receiving CD4 + T cells from CD-1 donor male or female mice. These results suggest that CD4 + T cells play an as yet unappreciated role in opioid analgesia, and may be a driver of sex differences therein.

Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences.

The processing of pain in the central nervous system is now known to have an important immune component, including T cells of the adaptive immune system. T cells have been shown to release endogenous opioids, and although it is well known that opioids have effects on T-cell populations, very little attention has been given to the converse: how T cells may affect opioid regulation. We find here that, in addition to displaying significantly increased baseline pain sensitivity across various pain modalities, T-cell-deficient mice (CD-1 nude, Rag1 null mutant, and Cd4 null mutant) exhibit pronounced deficiencies in morphine inhibition of thermal or inflammatory pain. Nude mice are also deficient in endogenous opioid-mediated analgesia, exhibiting no stress-induced analgesia from restraint. The relevant T-cell subpopulation seems to be CD4 T cells because adoptive transfer of them but not CD8 cells into nude mice rescues both the pain and morphine analgesia phenotypes. As previously reported, we also observe a sex difference in CD-1 mice, with females requiring 2- to 3-fold more morphine than males to produce equal analgesia. Nude mice display no sex differences in morphine analgesia, and the sex difference is restored in nude mice of either sex receiving CD4 T cells from CD-1 donor male or female mice. These results suggest that CD4 T cells play an as yet unappreciated role in opioid analgesia and may be a driver of sex differences therein.

Toll like Receptor (TLR)-4 as a Regulator of Peripheral Endogenous Opioid-Mediated Analgesia in Inflammation

BackgroundLeukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund’s adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contributing to tonic basal antinociception. In the later phase we hypothesized that toll-like-receptor-(TLR)-4 activation of monocytes/macrophages triggers opioid peptide release and thereby stimulates peripheral opioid-dependent antinociception.ResultsIn Wistar rats with CFA hind paw inflammation in the later inflammatory phase (48–96 h) systemic leukocyte depletion by cyclophosphamide (CTX) or locally injected naloxone (NLX) further decreased mechanical and thermal nociceptive thresholds. In vitro β-endorphin (β-END) content increased during human monocyte differentiation as well as in anti-inflammatory CD14+CD16- or non-classical M2 macrophages. Monocytes expressing TLR4 dose-dependently released β-END after stimulation with lipopolysaccharide (LPS) dependent on intracellular calcium. Despite TLR4 expression proinflammatory M1 and anti-inflammatory M2 macrophages only secreted opioid peptides in response to ionomycin, a calcium ionophore. Intraplantar injection of LPS as a TLR4 agonist into the inflamed paw elicited an immediate opioid- and dose-dependent antinociception, which was blocked by TAK-242, a small-molecule inhibitor of TLR4, or by peripheral applied NLX. In the later phase LPS lowered mechanical and thermal nociceptive thresholds. Furthermore, local peripheral TLR4 blockade worsened thermal and mechanical nociceptive pain thresholds in CFA inflammation.ConclusionEndogenous opioids from monocytes/macrophages mediate endogenous antinociception in the late phase of inflammation. Peripheral TLR4 stimulation acts as a transient counter-regulatory mechanism for inflammatory pain in vivo, and increases the release of opioid peptides from monocytes in vitro. TLR4 antagonists as new treatments for sepsis and neuropathic pain might unexpectedly transiently enhance pain by impairing peripheral opioid analgesia.

Endogenous Opioid-Mediated Analgesia Is Dependent on Adaptive T Cell Response in Mice

Pain is an inherent component of inflammation often accompanying immune response. A large spectrum of molecules released within the inflamed tissue induces pain by stimulating primary afferent neurons in situ. Activity of primary sensitive fibers can be counteracted by local opioid release by leukocytes. In this study, we investigated the endogenous regulation of CFA-induced inflammatory pain in the context of adaptive T cell immune response. The nociceptive response to mechanical stimuli was studied using von Frey filaments in mice immunized with OVA in CFA. The nociceptive response of nude versus wild-type mice was dramatically increased, demonstrating T cell deficiency associated with increased pain sensitivity. Based on adoptive transfer experiments of OVA-specific CD4(+) T lymphocytes into nude mice, we show that Ag-specific activated, but not resting T lymphocytes are responsible for the spontaneous relief of inflammation-induced pain following Ag challenge. The analgesia was dependent on opioid release by Ag-primed CD4(+) T lymphocytes at the inflammatory site. Indeed, T cell-mediated analgesia was inhibited by local injection of an opioid receptor antagonist, unable to cross the blood-brain barrier. Notably, we found opioid precursor mRNA to be >7-fold increased in Ag-specific activated CD4(+) T lymphocytes, as compared with resting T lymphocytes in vivo. Taken together, our results show that CD4(+) T lymphocytes acquire antinociceptive effector properties when specifically primed by Ag and point out analgesia as a property linked to the effector phase of adaptive T cell response.

No interactive effects of naltrexone and benzodiazepines on pain during phobic fear

Animal research has shown that anxiety may inhibit pain through the release of endogenous opioids. On the other hand, anxiety is often believed to exacerbate pain in clinical situations, and anxiety reduction has been shown to attenuate the affective component of pain. In the present study phobic anxiety was induced by confronting forty-eight spider phobic subjects with a spider, after which they received two mildly painful electrical stimuli at two different current levels. The benzodiazepine alprazolam (1 mg) was administered to investigate the influence on pain of a reduction in anxiety, while the role of endogenous opioids was studied by administering the opioid antagonist naltrexone (50 mg). Alprazolam resulted in lower anxiety and pain ratings during pain stimulation, supporting the idea that (presumably pain-related) anxiety may increase the experience of pain. Naltrexone did not influence pain and anxiety ratings, nor was there a significant interaction between the two pharmacological manipulations. These findings confirm previous evidence that phobic fear does not necessarily induce an endogenous opioid-mediated analgesia.

Exposure to the calls of predators of mice activates defensive mechanisms and inhibits consummatory behaviour in an inbred mouse strain

As two-minute exposures to the tape-recorded calls of barn and tawny owls activate endogenous opioid-mediated analgesia mechanisms in laboratory mice, the behavioural effects of the calls of a variety of predator and nonpredator species were ethologically assessed. While no clear effect could be seen on cage-orientated behaviour, the calls of the barn owl and tawny owl produced consistent increases in self-orientated, call-orientated and defensive behaviour indicating that these calls were recognised as belonging to predators. The call of the gull also produced an increase in defense, but, as this could be attributed to an increase in attend only, test animals may react to a change in stimulus properties without the gull call unequivocally representing a potential threat. These results indicate recognition of, and appropriate reaction to, the calls of known night-hunting, airborne primary predators of mice by an inbred laboratory strain.

The calls of murine predators activate endogenous analgesia mechanisms in laboratory mice

In view of the suggested role of endogenous analgesia mechanisms as an antipredator defense mechanism, the effects on nociception of exposure to the calls of various murine predatory and nonpredatory species were assessed. Data revealed that the calls of the Tawny Owl, Barn Owl and Common Gull all induced significant analgesia following exposure to 2 min of birdsong. Time course analysis revealed the analgesia induced by the Tawny Owl call to have a duration in excess of 40 min while the Barn Owl and Gull call-induced analgesias were much shorter lasting (approximately 10 min or less). Five mg/kg naloxone was found to attenuate the analgesia induced by the Tawny and Barn Owls but not the Common Gull. Together, these data suggest that brief exposure to the calls of night-hunting, aerial predators activate endogenous opioid-mediated analgesia mechanisms in mice.

Synergism between the analgesic actions of morphine and pentazocine

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of morphine, a mu-opiate receptor agonist and pentazocine, a kappa-opiate receptor partial-agonist was evaluated. Groups of 20 patients received either vehicle, morphine (2, 4, 8 or 16 mg), pentazocine (15, 30 or 60 mg) or a combination of morphine and pentazocine (2 mg or 4 mg and 15 mg or 30 mg, respectively). The combination of morphine and pentazocine produced a level of analgesia significantly greater than can be accounted for by simple addition of the analgesic effects of each opiate analgesic alone. We propose that the observed synergism between morphine and pentazocine is due to interaction between mu- and kappa-opioidergic components of endogenous opioid-mediated analgesia systems.

Prostaglandins inhibit endogenous pain control mechanisms by blocking transmission at spinal noradrenergic synapses

Spinal intrathecal injections of the nonsteroidal antiinflammatory analgesics (NSAIAs) indomethacin and acetylsalicylic acid, which inhibit prostaglandin synthesis, cause dose-dependent hypoalgesia in the rat. Intrathecal injections of prostaglandin-E2 (PGE2) produce dose-dependent hyperalgesia. To determine whether this action of prostaglandins on the central nervous system is mediated through pain-generating or analgesia pathways, we studied the effect of intrathecal PGE2 on endogenous opioid-induced analgesia. Intrathecal PGE2 antagonized the analgesia produced by both brain stimulation and intracerebroventricular morphine. In contrast, the NSAIAs synergized with brain stimulation and morphine-induced analgesia. The alpha-adrenergic antagonist phentolamine and the catecholaminergic selective neurotoxin 6-hydroxydopamine, used to block tonic catecholamine activity in endogenous opioid-mediated analgesia systems, prevented the hyperalgesia induced by intrathecal PGE2. Phentolamine did not, however, block the hyperalgesia caused by intradermal PGE2. These findings suggest that prostaglandins can block endogenous opioid-mediated analgesia systems by inhibiting the bulbospinal noradrenergic component of this analgesia pathway.

Desipramine enhances opiate postoperative analgesia

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid-mediated analgesia systems.

The role of stimulus intensity and stress in opioid-mediated analgesia

Rats exposed to a Pavlovian conditioning paradigm developed naloxone-reversible analgesia only when the intensity of a noxious unconditioned stimulus was suprathreshold and the level of stress was augmented. The time course of the onset of this conditioned analgesia was reproduced by systemic administration of morphine. These findings suggest that both a minimal level of stimulus intensity and stress are necessary for the activation of endogenous opioid-mediated analgesia.