Pain Physician 2011; 14:249-258 • ISSN 1533-3159

Narrative Review

Peripherally Acting and Clinical Implications for Pain Control

Nalini Sehgal, MD1, Howard Smith, MD2, and Laxmaiah Manchikanti, MD3

From: 1University of Wisconsin School of Medicine and 2 Public Health, Madison, WI; Albany receptors are widely expressed in the central and peripheral nervous system Medical College, Department of Anesthesiology, Albany, NY; 3Pain and in the non-neuronal tissues. Data from animal and human clinical studies support Management Center of Paducah, the involvement of peripheral opioid receptors in analgesia, especially in the presence Paducah, KY of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation Dr. Sehgal is Medical Director, Interventional Pain Program, University of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of Wisconsin School of Medicine and of chemokines and adhesion molecules, opioid -containing immune cells Public Health and Associate Professor, extravasate and accumulate in the injured tissues. Rehabilitation Medicine, Madison, WI. Dr. Smith is Associate Professor & Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate Academic Director of Pain Management, Albany Medical College, Department of these granulocytes to release opioid . Once secreted, opioid peptides bind Anesthesiology, Albany, NY. to and activate peripheral opioid receptors on sensory nerve fibers and produce Dr. Manchikanti is MedicalvDirector analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of of the Pain Management Center of pro-inflammatory neuropeptides. Paducah, Paducah, KY, and Associate Clinical Professor, Anesthesiology and Perioperative Medicine, University of Research has revealed that local application of exogenous opioid agonists produces a Louisville, Louisville, KY. potent effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central Address correspondence: Nalini Sehgal, MD, nervous system (CNS), and therefore centrally mediated side effects, such as respiratory University of Wisconsin School depression, mental clouding, altered consciousness, or addiction, are not associated of Medicine and Public Health, with peripheral opioid activity. This discovery has stimulated research on developing 600 Highland Avenue MC#2424, peripherally restricted opioid agonists that lack CNS effects. In addition, it has been Madison, WI 53595 E-mail: [email protected] recognized that opioid receptors modulate inflammation, and that opioids have anti- inflammatory effects. The anti-inflammatory actions of opioids are not well known For full disclosures, see page 255. or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid Manuscript received: 01/26/2011 analgesia and describe current research directed at developing novel treatments for Revised manuscript received: 05/05/2011 Accepted for publication: 05/10/2011 pain with improved side effect profiles.

Free full manuscript: Key words: Opioids, opioid receptors, opioid agonists, peripheral nervous system, www.painphysicianjournal.com peripheral opioid receptors

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pioids are potent that exert their described: mu (µ), delta (δ) and kappa (κ). These 3 pharmacological effects by binding and classes of opioid receptors are widely distributed in Oactivating specific receptors in the nervous the central nervous system (CNS). In addition to opioid system. Three distinct membrane bound receptor receptors in CNS, peripheral neurons, neuroendocrine subtypes with distinct behavioral characteristics are (pituitary, adrenals), immune, and ectodermal cells

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Peripheral Opioid Receptors (1) also express opioid receptors. These peripheral opioid receptors play a critical role in modulating pain Three types of opioid receptors are described, mu and inflammation. Potent analgesia after peripheral (µ), delta (δ) and kappa (κ). All 3 receptors modulate administration of opioids has been reported in animal pain and are expressed throughout the central nervous and human studies and new research is beginning to system (CNS). Animal studies have established presence elucidate peripheral mechanisms of opioid analgesia. of µ, δ and κ opioid receptors in nervous and nonner- Russell et al (2) demonstrated that the peripheral vous tissues outside the CNS. In 1987, Russell’s group in analgesic effect of opioids is mediated by activation of Germany (2) demonstrated opioid receptors on nerve opioid receptors in the peripheral nervous system (PNS) fibers in the knee joint of the cat and observed that and other cells, especially in presence of inflammation. locally administered opioid agonists decrease the fre- Opioid peptides such as β endorphin and Met- quency of spontaneous discharges in small diameter have been found in human synovium, mast cells, nerve fibers. It was suggested that may exert a keratinocytes, and immune cells (3-9). peripheral “analgesic” effect by binding to re- containing immune cells have been shown to migrate ceptors on primary afferent fibers in peripheral sites. to sites of tissue inflammation (10-12), and release Animal and human studies since then have demonstrat- opioid peptides in response to stress, or release agents ed opioid receptors in fine cutaneous nerve fibers (28, such as corticotrophin-releasing factor, chemokines, 29), bone and joint tissue (30), keratinocytes (7,9), and cytokines, and norepinephrine (13-17). Once secreted, immune cells (1). Opioid receptors are expressed in the opioid peptides bind to peripheral opioid receptors small-, medium- and large-diameter dorsal root gangli- expressed on sensory nerve fiber terminal endings on (DRG) neurons (28,31). Mu opioid receptors (MOR) (18-20), activate and produce analgesia by inhibiting are expressed in the enteric neurons in the gut (32) and the excitability of sensory nerves, and /or inhibit the play an important role in gut nociception, motility and release of pro-inflammatory neuropeptides (substance secretion. MOR have also been described in epidermal P, calcitonin gene related peptide) (21,22). Clinically and dermal layers of normal human skin and in nerve significant analgesia is obtained from this neuro- fibers of human dental pulp (9,33). In addition, µ, δ and immune interaction without the accompanying side κ receptors have been demonstrated in the capsule/ effects commonly associated with centrally mediated synovium and periosteum (30). opioid analgesia, such as respiratory depression, nausea, Opioid receptors are synthesized in the DRG and cognitive disturbances, tolerance, and addiction (23). transported centrally and peripherally to the nerve Endogenous immune cell derived opioids do not terminals. They belong to the family of G-protein- readily produce cross-tolerance to , but rather coupled receptors with 7 trans-membrane domains. prevent development of tolerance at peripheral opioid Endorphins and locally administered opioids bind and receptors (24-26). The evidence for therapeutically activate the opioid receptors in the periphery. On ac- relevant opioid-induced analgesia at peripheral sites tivation, the receptors couple to inhibitory G-proteins of inflammation is accumulating. Strategies and (Gi/o) and inhibit cyclic AMP production and/or directly treatments that selectively attract opioid producing interact with K+, Ca2+, and other ion channels in the immune cells, increase expression of opioid receptors membrane. Analgesia results from decreased nocicep- in damaged tissues in the periphery, and selectively tor excitability, reduced action potential propagation, activate peripheral opioid receptors appear to have and decreased release of excitatory pro-inflammatory immense therapeutic potential. Furthermore, opioids neuropeptides (substance P and calcitonin gene relat- exert anti-inflammatory effects via changes in cellular ed peptide) at central and peripheral nerve terminals activation and cytokine expression (27) and may have (21,26). Opioids injected locally into soft tissues or joints a role in the treatment of inflammatory arthropathy, produce potent and receptor-specific analgesic effects inflammatory bowel disease, and other inflammatory that are mediated by peripheral opioid receptors, oc- skin disorders. cur in the absence of central analgesic activity, and are This article reviews current research on peripheral reversible (34). Pain relief has been reported opioid receptors, opioid peptides, and opioid produc- after knee arthroscopy on intra-articular injections of ing immune cells; modulation of pain and inflamma- morphine (35-37) and after submucosal injection of tion by opioids; and development of peripherally active morphine in patients undergoing dental surgery (38). opioid drugs.

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These and similar studies suggest a role for peripheral number of opioid-peptide producing cells. opioid receptors independent of centrally mediated an- Opioid peptide expressing leukocytes: Opioid pep- algesic activity (39). tide-containing leukocytes are T and B lymphocytes, The anti-nociceptive effects of opioids are mark- granulocytes, and monocytes/macrophages (19). These edly enhanced in the presence of inflammation and are leukocytes contribute to endogenous pain inhibition mediated by peripheral -specific mecha- at different stages of inflammation. In early inflam- nisms (29,40,41). Although opioid receptor-mediated mation, granulocytes are the predominant opioid pep- analgesia is enhanced, opioid receptor transcription in tide-producing leukocytes, while in later stages opioid DRG is not enhanced in the early stages of inflammation peptides are expressed mainly by monocytes or macro- (42). At later stages, however, the number of peripheral phages (51). Different types of opioid peptides are re- opioid receptors appears to increase and may enhance leased from immune cells and include beta-endorphin opioid efficacy. In animal studies, local administration (END), Met-enkephalin (ENK), and -A (DYN), of opiates into an inflamed paw produces dose-related, although the predominant opioid peptide involved in stereospecific analgesia restricted to the injected area immune-cell mediated antinociception is thought to (43). Peripheral analgesia mediated through the MOR be END (52). These peptides are derived from distinct has been demonstrated in a variety of clinical settings, genes and respective precursors, i.e., pro-opiomela- with the preponderance of data generated with ar- nocortin (POMC), pro-enkephalin, and pro-dynorphin throscopic procedures. Morphine peripheral analgesia (53). Leukocytes contain and process the precursors appears to depend on activation of the P13Kgama/AKT/ into functionally active opioid peptides. Studies have nNOS/NO/KATP signaling pathway (44). The MOR has shown that both β endorphin and mRNA encoding also been shown to play a role in the control of gut in- its precursor pro-opiomelanocortin (POMC) are pres- flammation (32 45). Schramm and Honda (46) showed ent in immune cells (14,53). Increased expression of that under normal conditions, δ-opioid receptor ago- POMC mRNA and β endorphin has been demonstrated nists enhance the effect of µ-opioid receptor agonists in stimulated lymphocytes and lymphocytes of animals in the periphery, and local co-administration of δ- and with inflammation (15). Labuz et al (54) showed that µ-opioid receptor agonists may improve results of pe- 30% to 40% of immune cells accumulating at injured ripheral opioid therapy for the treatment of pain. A pe- nerves expressed opioid peptides such as beta-endor- ripherally selective kappa agonist has been reported to phin, Met-enkephalin, and dynorphin-A. be effective in relieving the pain associated with chronic Recruitment of opioid peptide-containing im- pancreatitis (47). Furthermore, different regions of the mune cells: Opioid containing immunocytes migrate body may exhibit different effects following the activa- to inflamed tissue in a complex multistep process of tion of peripheral opioid receptors. In the rat pain mod- recruitment, adhesion, and extravasation controlled els of Sanchez et al (48), peripheral opioid receptors by adhesion molecules that are up-regulated on ves- seem to participate in hypertonic saline (HS)-induced sel endothelia and co-expressed by opioid-containing masseter pain, whereas only central opioid receptors re- immunocytes (19). The adhesion process consists of 3 duced the nociception in the gastrocnemius and triceps. main steps: tethering, triggering, and latching, and Their results suggest that the use of peripheral opioids involves sequential interaction with separate classes may be more advantageous than central opioids for of adhesion molecules (11,55). For instance, selectins treatment of orofacial muscular pain (48). mediate the rolling of leucocytes along the endo- thelial cell wall (56). Leukocytes are then activated Opioid Peptides and Inflammation by chemokines released from inflammatory cells and Inflammation not only increases expression, trans- presented on the endothelium. Integrins and adhe- port, and accumulation of peripheral opioid receptors sion molecules mediate adhesion of leukocytes to en- on peripheral terminals of sensory nerves, but also trig- dothelial cells and transmigration through the vessel gers migration of opioid containing immunocytes (49). wall into inflamed tissue (11,57). Neurokinins (e.g., Immune cells containing opioid peptides migrate to the substance P) contributes to leukocyte recruitment inflamed tissue and release endogenous opioid pep- in inflammation by upregulating adhesion molecule tides that bind and activate peripheral opioid receptors expression through neurokinin-1 (NK1) receptors on to produce potent analgesic effect (49,50). The degree endothelial cells; augmenting chemokine production; of endogenous pain inhibition is proportional to the or chemotaxis through NK1 receptors on leukocytes

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Modulation of Pain and Inflammation (58). Interference with the recruitment of opioid-con- taining immune cells into inflamed tissue by blockade Tissue injury is associated with an inflammatory re- of adhesion molecules or by intrathecal morphine in- sponse, nociceptor activation, and pain. In early stages jection reduces endogenous analgesia. For example, endogenous hyperaglesic mediators are produced, in- blocking selectins (cell surface glycoprotein) results cluding cytokines, chemokines, nerve growth factor, in reduced numbers of β endorphin-containing cells, bradykinin, prostaglandin, and ATP. Local inflammation reduced quantity of β endorphin in inflamed tissues, also leads to simultaneous secretion of analgesic me- and reduced stress and corticotrophin-releasing factor diators such as opioid peptides, somatostatin, endocan- (CRF) induced peripheral analgesia (56,59). The migra- nabinoids, and certain cytokines. The immune system is tion of activated immune cells to inflamed tissues di- a source of opioid peptides and plays an important role rected by chemokines and adhesion molecules may be in control of inflammatory pain. Inflammatory pain can hampered by treatment with anti-adhesion molecules be effectively controlled by an interaction of opioid re- and this may have implications in the treatment of ceptors on peripheral sensory nerve terminals with opi- pain in individuals with autoimmune disease on novel oid peptides released from immune cells upon stressful immunosuppressive drugs (11,19). stimuli. These mechanisms are based on the interaction Secretion of opioid peptides by immunocytes: between the immune and nervous systems. The initi- Infiltrating lymphocytes express, contain and release ation of pain and its control may be regarded as the opioid peptides within inflamed tissues. Production of body’s response to prevent further injury, to support opioid peptides in immunocytes is inherently linked healing, and to return to normal function as quickly as with activation of immune cells (13,14,56). Memory possible. type T cells that contain opioids are present within in- Expression of peripheral opioid receptors: Periph- flamed tissues; naïve cells are not present in inflamed eral inflammation upregulates opioid receptor mRNA tissue and do not contain opioid peptides (14). Opi- (32,64); the synthesis of peripheral opioid receptors in oid peptide is released from the immune cells upon DRG neurons and axonal transport is increased, and stimulation with CRF, noradrenaline (16), tumor necro- there is enhanced G-protein coupling at peripheral sis factor alpha (TNFα) (60), and interleukin 1beta (IL- nerve terminals in the presence of tissue inflammation 1beta), and the corresponding receptors are present (65-67). The expression of receptors changes depend- on opioid-expressing leukocytes (13,14,16,49,61,62). ing on receptor type and duration of inflammation. In Multiple areas in the brain, inhibitory interneurons case of MOR, there is an increase in both the number in the spinal cord dorsal horn, and immune cells in of neurons expressing MOR, and the number of MOR subcutaneous tissues, but not the peripheral sensory per neuron, while affinity of opioid agonists to MOR neurons, co-express CRF receptors and opioid peptides remains unchanged (67). The upregulation of sensory (63). Adrenergic α1, α2, and β2 receptors are expressed neuron MOR is governed by nerve growth factor (NGF) on β-endorphin-containing inflammatory cells in close which is also implicated in inflammatory pain (68). In proximity to sympathetic nerve fibers in inflamed addition, the number of nociceptor nerve endings in- paws. The release of opioid peptides is calcium depen- crease and the perineural barrier is disrupted, facilitat- dent and opioid receptor specific. Secretion requires ing access of opioid agonists to their receptors, result- intracellular calcium mobilization and activation of ing in enhanced peripheral analgesic efficacy of opioids phosphoinositol-3-kinase and p38 mitogen activated in inflammation (19,69). The effective number of pe- kinase. The immune cells return to the local lymph ripheral opioid receptors does not increase during early node after opioid peptide is released and the cells are stages of inflammation (42). At later stages, however, depleted of the peptide. Consistent with this model, the number of peripheral MOR appears to increase and systemic immunosuppression may lead to impaired en- may enhance opioid efficacy (42,65). dogenous analgesia as competent immune cells are es- Activation of peripheral opioid receptors: There sential to achieve release of endogenous opioid pep- appears to be an integral link between infiltrating im- tides within inflamed tissue. Complicating this further mune cells and increased presence of opioid receptors is the observation that exogenous opioids may impair on sensory nerves (14). Endogenous opioid peptides immune cell function, although there is some evidence released from immune cells bind to opioid receptors to suggest that endogenous opioid peptides do not on peripheral terminals of sensory nerves to evoke share this immunosuppressive effect (62). potent analgesic responses in animals with induced

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inflammation (40,41). Inflammation-induced “activa- creases the efficacy of peripheral endogenous opioid tion” of the opioid receptors is of significance in the analgesia. This was demonstrated by an experimental manifestation of peripheral opioid anti-nociception; study in rats, where continuous intrathecal morphine in particular, receptor activation occurs in the early infusion increased paw pressure threshold (indicating stages of inflammation when the infiltration of the antinociception) without changing inflammation. The tissue with immune-competent cells is just beginning number of beta-endorphin-containing cells and cold (61). Machelska (70) showed that in early (within 6 water swim-stress induced endogenous analgesia were hours) inflammation, leukocyte-derived beta-endor- significantly reduced in intrathecal morphine-treated phin, Met-enkephalin, and activate pe- rats compared with controls suggesting interplay of ripheral mu-, delta- and kappa-receptors to inhibit central and peripheral mechanisms of pain control. An nociception. In addition, central opioid mechanisms effective central inhibition of pain apparently signals a seem to contribute significantly to this effect. At later reduced need for recruitment of opioid containing im- stages (4 days), antinociception is exclusively produced mune cells to the injured site (71). by leukocyte-derived beta-endorphin acting at periph- Peripherally Acting Opioids eral mu- and delta- receptors (70). These findings in- dicate that peripheral opioid mechanisms of pain in- Although currently there are no specific periph- hibition gain functional relevance and become more erally acting opioids available in the United States, prevalent with duration and severity of inflammation investigators continue to work on developing novel (19). Corticotropin-releasing hormone (CRH) is an en- potential agents. The novel D-amino acid tetrapep- dogenous trigger of these effects at both stages. In a tide CR665, when injected intravenously in nanomolar mouse model of neuropathy, selective stimulation of range, elicited potent analgesia in the mouse writhing immune cells by local application of CRF led to opi- test without producing motor impairment (72). The oid peptide mediated activation of opioid receptors peripherally restricted kappa-agonist FE200665, also in damaged nerves, and abolition of tactile allodynia known as CR665, has completed Phase I clinical tri- suggesting that selective targeting of opioid-contain- als and currently in Phase II (73). Arendt-Nielsen et al ing immune cells promotes endogenous pain control (74) compared the analgesic efficacy of the peripheral and offers novel opportunities for treating painful kappa-opioid receptor agonist CR665 to in neuropathy (54). A study in a rat model showed that a multi-modal, multi-tissue experimental human pain the majority of the C and C/A delta nociceptors inner- model. CR665 had a selective effect on visceral pain. vating inflamed skin were opiate sensitive, and their Oxycodone exhibited a generalized effect, elevating excitability was attenuated by direct application of thresholds for cutaneous, deep somatic, and visceral morphine to their receptive fields, lending support to pain stimulation (74). the evidence that topical morphine acts through pe- 6-amino acid-substituted derivatives of 14-O-meth- ripheral opioid receptors to inhibit activity of cutane- yloxymorphone were described as MOR agonists with ous nociceptors in inflamed tissues (29). restricted penetration to the central nervous system Inflammation and perineural barrier: The perineu- (75,76). Obara et al (77) assessed the antinociceptive rium is a crucial determinant for peripheral opioid anal- effects of the 6-amino acid conjugates (glycine and gesia and is impervious in the absence of inflammation. ), α- or β-orientated, 14-O-methyloxy- Inflammation increases the permeability of the peri- morphone in rat models of inflammatory pain (induced neurium, thereby exposing the receptors at the sensory by local intraplantar (IPL) formalin injection and neuro- nerve terminals to endogenous and exogenous opioids. pathic pain (produced by ligation of the sciatic nerve) Peripheral opioid antinociception and perineural leak- after local IPL administration directly into the injured age occur simultaneously at a very early stage (within hindpaw and compared their antinociceptive effects to 12 hours) of the inflammatory reaction. Evidence sup- morphine. Local IPL administration of the new deriva- ports the observation that the efficacy of locally applied tives in rats with neuropathic pain induced by sciatic hydrophilic or lipophilic neuromodulatory compounds nerve ligation produced anti-allodynic and anti-hyper- can be improved dramatically by the concomitant mod- algesic effects; however, the anti-nociceptive activity ulation of perineural permeability (69). was lower than that observed in inflammatory pain Effect of central afferent blockade on peripheral (77). Moreover, the local opioid antinociceptive effects endogenous analgesia: Central inhibition of pain de- were significantly attenuated by naloxone methiodide,

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a peripherally acting opioid receptor antagonist, dem- ways may contribute to the anti-inflammatory effect of onstrating that the effect was mediated by peripheral these drugs. However the hypothalamic-pituitary-adre- opioid receptors (77). Obara et al (77) suggested their nal axis, a major point of neuro-immune convergence, data indicate that the peripherally restricted 6-amino is only partially involved in the anti-inflammatory ac- acid conjugates of 14-O-methyloxymorphone elicit tions of opioids. anti-nociception after local administration, being more Painful skin conditions: A topical route of anal- potent in inflammatory than in neuropathic pain. gesia might be extremely beneficial for children with Synthesis and opioid activity of analogues painful skin lesions, including burns or post-surgical including N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)- wounds, especially where acute inflammatory pain is a 4-piperidyl)] propenamide (IQMF-4), showed an inter- major symptom and effective analgesia is a major clini- esting anti-nociceptive activity. Intraperitoneally (IP) cal problem. Topical morphine gel in 2 children with administered, it was as effective as fentanyl or mor- epidermolysis bullosa provided rapid reduction in pain phine, being less potent than fentanyl, but more so scores without any reported adverse effects or toler- than morphine (78). When IQMF-4 was administered IP, ance. More studies are required to study the utility of naloxone methiodide, a peripherally acting antagonist, peripheral opioid analgesia in children (79). was able to completely block its antinociceptive effect, Neuropathic pain: Local application of mu-,delta- whereas, after intracerebroventricular (i.c.v.) adminis- and kappa-opioid agonists produced anti-allodynic and tration, the blockade was only partial. Although more anti-hyperalgesic effects in a dose dependent manner assays are required, these results suggest that IQMF-4 in animal models of neuropathic pain. The effective appears to be a potent analgesic compound with an in- dose (ED) range of mu- and kappa-agonists required teresting peripheral component, with a reduced ability to induce analgesia in neuropathy was much higher to induce dependence (78). than the ED for inflammation (50); delta-agonists were effective in the same dose range in both pain models Clinical Implications supporting the use of opioid peptides, especially delta- The inflammation-induced activation of opioid agonists in treating chronic pain. These effects were production and the release of endogenous opioids mediated by peripheral opioid receptors localized at from immune cells may lead to novel approaches for the site of tissue/nerve injury (80). the development of peripherally acting analgesics. In Inflammatory arthropathy: Kappa-opioids have an animal model of inflamed knee joint, intra-articu- a powerful anti-inflammatory effect and have been lar injection of mu- and kappa- but not delta- opioid shown to attenuate arthritis in a dose dependent, agonists, produced a dose dependent blockade of au- stereoselective, antagonist-reversible manner, reduc- tonomic response to a noxious stimulus indicating that ing disease severity by as much as 80% (27). Mu- and opioids, by an action at µ and κ receptors, can exert delta- opioid agonists, on the other hand, have thera- a direct anti-hyperalgesic action at the terminals of peutic anti-inflammatory activity at near toxic doses. primary afferents projecting to a region of inflamma- Kappa-opioids act at multiple sites in the inflammatory tion (34). A double blind, crossover study showed that cascade, and exert their anti-inflammatory actions by morphine-6-beta-glucuronide (M6G) in doses that lack reducing expression of the adhesion molecule, inhibit- CNS effects, exerts anti-hyperalgesic effects in inflam- ing cell trafficking, reducing release and expression of matory pain through activation of peripheral opioid re- tumor necrosis factor (TNF), and altering expression of ceptors. Since this occurs at concentrations that do not mRNA and levels of SP and CGRP protein in joint tissue cause central opioid effects, M6G might be useful as (27). Neuropeptides (SP and CGRP) have been shown a peripheral opioid analgesic (39). These observations to play a role in the pathogenesis and maintenance of offer strong support for a peripheral action of opioids experimental arthritis and are strongly implicated in in inflammation-induced /pain. Opioid inflammation and arthritis. These neuropeptides are agonists have powerful anti-inflammatory properties released at afferent nerve terminals in the synovial tis- and they exert their action in the periphery via opioids sues. Kappa-opioids are therapeutic during disease on- receptors found on immune cells and neural cells. The set and most likely alter cellular activation and cytokine close spatial and functional association between nerves expression. Kappa opioids have increased potency in fe- and immune cells suggests that modulation of neuro- males compared to males, which may be an advantage immune interactions or neural pro-inflammatory path- in the treatment of inflammatory arthritis. Peripherally

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acting kappa opioids may prove to be a potent new with peripherally restricted mu, delta, and kappa ago- treatment for rheumatoid arthritis and other inflam- nists will be needed in the future to evaluate utility in matory arthritis. neuropathic pain, cancer pain, and inflammatory pain- Inflammatory bowel disease: MOR have been ful disorders of gut, skin, etc. Finally, the mechanisms shown to play a role in control of gut inflammation of endogenous pain inhibition by opioid peptide-pro- and MOR agonists may become novel treatments for ducing immune cells may be important for understand- inflammatory bowel disease (IBD). Subcutaneous ad- ing pain in immune compromised states such as cancer, ministration of selective MOR agonists, such as DALDA diabetes, and acquired immunodeficiency syndrome and [D-Ala2,NMe-Phe4,Gly5-ol]enkephalin (DAMGO), (AIDS). significantly reduced inflammation in 2 experimental Disclosures models of colitis in mice. The anti-inflammatory effect was completely abolished by naloxone. The mechanism Author Contributions: Dr. Sehgal had full access underlying the anti-inflammatory effect of MOR in the to all the data in the study and takes responsibility for colon is suggested to be mediated through regulation the integrity of the data and the accuracy of the data of cytokine production and T cell proliferation, both of analysis. Drs. Sehgal, Smith and Manchikanti designed which play a role in the development of colon inflam- the study protocol. Dr. Sehgal managed the literature mation in IBD in humans and mice (45). searches and summaries of previous related work and wrote the first draft of the manuscript. All other au- Summary thors provided revision for intellectual content and fi- Experimental and clinical research has demon- nal approval of the manuscript. strated that opioids can produce potent and receptor Conflict of Interest: All authors have no conflicts specific analgesic effects outside the central nervous of interest to report. None of the authors of the manu- system. Peripheral analgesia mediated through opioid script received any remuneration. Further, the authors receptors has been demonstrated in a variety of clinical have not received any reimbursement or honorarium in settings. Receptor localization studies using human tis- any other manner. However, all the authors are mem- sue have corroborated the presence of opioid receptors bers of the American Society of Interventional Pain Phy- in the periphery and their endogenous ligands, opioid sicians (ASIPP) and practicing interventional pain phy- peptides, have been discovered in immune cells within sicians. Dr. Manchikanti is the Chairman of the Board inflamed tissue. Experimental and clinical research has and founder of ASIPP, which was responsible for the shown that under conditions of inflammation, onset of National All Schedules Prescription Electronic Reporting peripherally mediated opioid analgesia is delayed, but Act (NASPER) legislation and its implementation. once initiated, is of long duration. These findings open Funding/Support: TNo funding/support. up the possibility of developing an entirely novel gen- Acknowlegments eration of peripherally active opioid analgesics that will selectively block pro-algesic mediators, or enhance the The authors also wish to thank Tom Prigge, MA for transport and release of immune-derived opioid pep- manuscript review, and Pya Seidner for her assistance in tides into injured tissue and stimulate the endogenous preparation of this manuscript. We also would like to peripheral analgesic system to induce effective periph- thank the editorial board of Pain Physician for review eral analgesia without central side effects. Clinical trials and criticism in improving the manuscript.

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