Gavril W. Pasternak

Pharmacological mechanisms of opioid analgesics.

The description of multiple classes of opioid receptors has had a major impact on our understanding of the mechanisms of analgesia. Three major classes of opioid receptors have been defined: mu, kappa, and delta. The mu receptors have been further subclassified into two distinct subtypes (mu 1 and mu 2), as have the delta receptors (delta 1 and delta 2). Kappa receptors have been subdivided into kappa 1, kappa 2, or kappa 3 subtypes. All of these subtypes modulate pain perception, with the exception of the kappa 2 receptor, which has not been adequately examined. Supraspinal systems have been described for mu 1, kappa 3, and delta 2 receptors while mu 2, kappa 1, and delta 1 receptors modulate pain at the spinal level. In addition to their ability to act independently, the various systems also interact synergistically with each other. Thus, the relief of pain involves the complex interaction of at least six receptor systems. This review discusses the implications of opiate receptor multiplicity on the control of pain.

Strategies to Manage the Adverse Effects of Oral Morphine: An Evidence-Based Report

Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria, a substantial minority of patients treated with oral morphine (10% to 30%) do not have a successful outcome because of (1) excessive adverse effects, (2) inadequate analgesia, or (3) a combination of both excessive adverse effects along with inadequate analgesia. The management of excessive adverse effects remains a major clinical challenge. Multiple approaches have been described to address this problem. The clinical challenge of selecting the best option is enhanced by the lack of definitive, evidence-based comparative data. Indeed, this aspect of opioid therapeutics has become a focus of substantial controversy. This study presents evidence-based recommendations for clinical-practice formulated by an Expert Working Group of the European Association of Palliative Care (EAPC) Research NETWORK: These recommendations highlight the need for careful evaluation to distinguish between morphine adverse effects from comorbidity, dehydration, or drug interactions, and initial consideration of dose reduction (possibly by the addition of a co analgesic). If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, opioid rotation, or switching route of systemic administration. The approaches are described and guidelines are provided to aid in selecting between therapeutic options.

Retention of Supraspinal Delta-like Analgesia and Loss of Morphine Tolerance in δ Opioid Receptor Knockout Mice

Gene targeting was used to delete exon 2 of mouse DOR-1, which encodes the delta opioid receptor. Essentially all 3H-[D-Pen2,D-Pen5]enkephalin (3H-DPDPE) and 3H-[D-Ala2,D-Glu4]deltorphin (3H-deltorphin-2) binding is absent from mutant mice, demonstrating that DOR-1 encodes both delta1 and delta2 receptor subtypes. Homozygous mutant mice display markedly reduced spinal delta analgesia, but peptide delta agonists retain supraspinal analgesic potency that is only partially antagonized by naltrindole. Retained DPDPE analgesia is also demonstrated upon formalin testing, while the nonpeptide delta agonist BW373U69 exhibits enhanced activity in DOR-1 mutant mice. Together, these findings suggest the existence of a second delta-like analgesic system. Finally, DOR-1 mutant mice do not develop analgesic tolerance to morphine, genetically demonstrating a central role for DOR-1 in this process.

Morphine-6-glucuronide, a potent mu agonist

The 3- and the 6-glucuronides of morphine have been examined in binding studies and in vivo. The 3-glucuronide had poor affinity in all binding studies whereas the 6-glucuronide potently labeled mu, but not delta or kappa receptors with affinities similar to morphine. Microinjections of the 3-glucuronide directly into the periaqueductal gray were without effect. The 6-glucuronide, on the other hand, was up to 20-fold more potent than morphine following microinjections in the same region. High doses of the 6-glucuronide produced profound seizure activity. All 6-glucuronide actions were sensitive to the opiate antagonist naloxone.

Minireview: Multiple MU opiate receptors

In addition to morphine-selective mu2 and enkephalin-preferring delta sites, recent evidence supports the presence within the central nervous system of a common site with very high affinity for both enkephalins and opiates termed tht mu1 site. This concept of a common, very high affinity site for multiple neurotransmitters is a unique concept in neuropharmacology, differing from classical transmitter systems which possess multiple receptor classes for a single transmitter. This review will address both the biochemical and pharmacological evidence supporting the existence of this site.

The NMDA Receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-l-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids

&NA; Once daily s.c. administration of 5 mg/kg morphine, a mu‐opioid agonist, or U50488H (U50), a kappa1‐opioid agonist, for 5 days in male CD‐1 mice results in a 2–3‐fold shift to the right of the respective analgesic (tail flick) dose‐response curves, indicating the development of tolerance. Concurrent s.c. administration of the competitive NMDA receptor antagonist, LY274614 (LY), at 24 mg/kg/24 h infusion (osmotic pump) or 6 mg/kg i.p. once daily attenuates the development of morphine tolerance, when the response to saline plus morphine is compared on day 5 with LY plus morphine. Using this paradigm, once daily administration of either the non‐competitive NMDA antagonist, MK‐801, at 0.3 mg/kg i.p. or the nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine (NorArg), at 1 mg/kg i.p. twice daily attenuated the development of morphine tolerance. None of these drugs modify the tail‐flick response or alter the ED50 for morphine. In contrast, co‐administration of LY, MK‐801 or NorArg, as above, failed to attenuate the development of tolerance to U50 or to the kappa3‐opioid agonist, naloxone benzoylhydrazone (NalBzoH). These results suggest that mu‐opioid tolerance but not kappa1‐ or kappa3‐opioid tolerance involves the mediation of NMDA receptors and the nitric oxide system.

Retention of heroin and morphine–6β–glucuronide analgesia in a new line of mice lacking exon 1 of MOR–1

Morphine produces analgesia by activating mu opioid receptors encoded by the MOR–1 gene. Although morphine–6β–glucuronide (M6G), heroin and 6–acetylmorphine also are considered mu opioids, recent evidence suggests that they act through a distinct receptor mechanism. We examined this question in knockout mice containing disruptions of either the first or second coding exon of MOR–1. Mice homozygous for either MOR–1 mutation were insensitive to morphine. Heroin, 6–acetylmorphine and M6G still elicited analgesia in the exon–1 MOR–1 mutant, which also showed specific M6G binding, whereas M6G and 6–acetylmorphine were inactive in the exon–2 MOR–1 mutant. These results provide genetic evidence for a unique receptor site for M6G and heroin analgesia.

Individual variability in the response to different opioids: report of five cases

Although it is widely appreciated that patients can demonstrate highly variable responses to different opioid drugs, there have been few detailed descriptions of this phenomenon. To illustrate this variability, we present 5 patients, 4 with cancer pain and 1 with non-malignant pain, who underwent dose titration with more than 1 opioid and developed markedly different responses to each. In every case, dose escalation led to successful treatment with 1 opioid and to intolerable side effects without adequate relief with others. The existence of this individual variability in the response to different opioids has important implications for both clinical practice and current understanding of opioid pharmacology in man. It contradicts the view that any opioid is inherently more efficacious than any other, suggests that patients who fail to obtain adequate pain relief at maximally tolerated doses of 1 opioid may benefit from an alternative drug, and underscores the potential importance of genetic factors as a determinant of opioid response.

Selective loss of δ opioid analgesia and binding by antisense oligodeoxynucleotides to a δ opioid receptor

Antisense oligodeoxynucleotides (18-20 bases) to a cloned delta opioid receptor (DOR-1) lower delta binding in NG108-15 cells by 40%-50%. Changing 4 bases to generate a mismatch antisense oligodeoxynucleotide or mixing the corresponding sense and antisense oligodeoxynucleotides prior to treatment of the cells eliminates the inhibition of binding, confirming the specificity of the response. In vivo, an antisense oligodeoxynucleotide to DOR-1 given intrathecally lowers delta, but not mu or kappa 1 spinal analgesia. The mismatch antisense oligodeoxynucleotide is inactive. Delta analgesic sensitivity gradually returns by 5 days after the last antisense treatment, indicating the lack of irreversible damage or toxicity. These studies demonstrate that DOR-1 mediates delta analgesia at the level of the spinal cord and confirm at the molecular level traditional pharmacological studies implying distinct receptor mechanisms for delta, mu, and kappa 1 analgesia. The use of antisense approaches may prove valuable in understanding the receptors mediating opioid pharmacology.

Ontogeny of opioid pharmacology and receptors: High and low affinity site differences

The development of the high affinity binding of a variety of opiates and enkephalins is distinct from low affinity binding. During the first 2 weeks after birth, low affinity binding in both brain and spinal cord remains relatively constant while high affinity binding increases up to 3-fold. Differences in the development of analgesic and respiratory sensitivity to opiates are also found. Whereas morphine, beta-endorphin and D-Ala2-Met5-enkephalin-amide depress respiratory rates in 2-day old rats at doses equal to or lower than those active in 14-day old rats, morphines analgesic ED50 is 40-fold greater in 2-day old than in 14-day old rats. Similarly, beta-endorphin and D-Ala2-Met5-enkephalinamide are analgesic in 14-day old rats but not 7-day old rats. The small effect of spinal transections on morphine analgesia in 14-day old rats suggests that the change in analgesic sensitivity is at a segmental spinal level and not a result of descending pathways. These results suggest an interesting correlation between high affinity binding and analgesia and between low affinity binding and respiratory effects.