Hyperalgesia
Morphine-induced hyperalgesia appears to have a distinct pathway from tolerance. Hyperalgesia requires microglia. Specifically, morphine-induced hyperalgesia requires the expression of P2X4 receptor in the microglia. Chronic exposure to morphine causes an increase in P2X4 receptor expression by a p-receptor-dependent mechanism. P2X4 receptor stimulation results in the release of brain-derived neurotrophic factor (BDNF). BDNF through TrkB downregulates a K+-CL cotransporter (KCC2) expression in lamina I neurons causing an impairment in CL extrusion through a p-receptor-independent mechanism. So, a p-receptor-dependent mechanism is required to activate the microglia, but a p-receptor-independent mechanism is responsible for the microglia-neuron signaling. Toll-like receptor 4 (TLR4) was not involved in the p-receptor independent mechanism.28
TLR4 does play a role in the antinociceptive and hyperalgesic effect of morphine. TLR4 is predominantly expressed by microglia and is typically considered the receptor that senses endotoxin (lipopolysaccharide [LPS]). It is also the receptor responsible for the establishment of and maintenance of ongoing neuropathic pain by the release of substances released from neuron damage.29 Activation of TLR4 activates the ceramide pathway in glial cells which results in the activation of PI3k/Akt, NF-кВ, and MAP kinase (МАРК).2 Inflammatory cytokine overexpression and pain hypersensitivity occur. Morphine-3-glucoronide (M3G), an otherwise inactive morphine metabolite, activates TLR4 and results in opposing acute and chronic opioid analgesia, contributing to opioid-induced hyperalgesia, dependence, and reward.230 This has been shown in both the spinal cord and the PAG.31 Interference with the TLR4 receptor via multiple mechanisms potentiates the magnitude and duration of morphine analgesia.32
In animal models, opioid exposure has been shown to result in increased latent pain sensitization. A single opioid exposure activates NMDA-dependent pronociceptive systems, leading to long-term pain vulnerability after analgesia.33 In animal models, 7 days after an inflammatory event, a second inflammatory event creates a hyperalgesic response. This hyperalgesic response is exaggerated by exposure to fentanyl during the first inflammatory event. NMDA receptor blockade prevents this central sensitization event.34 Another animal model showed that a small dose of heroin was ineffective at producing hyperalgesia, but when given several days after opioid exposure hyperalgesia ensued. Hyperalgesia was prevented by NMDA receptor blockade.35 The inflammatory system is also impacted by MOP priming. After repeat MOP activation, prostaglandin E, (PGE2) administration results in markedly prolonged hyperalgesia. These findings were still present after 1 month.36 Similarly, 5-day opioid exposure 10 days after nerve injury prolonged injury-induced pain hypersensitivity for months after the cessation of morphine.37 The morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of IL-1(3 from microglia were responsible. A “two-hit hypothesis” from the microglia—the first from the nerve injury and the second from the opioid exposure—is likely responsible for this prolonged pain response.37
Non-nociceptive environmental stress may also play a role in the priming of the microglia cells. Non-nociceptive environmental stress typically leads to the release of endogenous opioids. However, repetitive non-nociceptive environmental stress prolonged hyperalgesia after opioid pretreatment for up to 4 months.33
Endocrine Disruption
Opioid administration—particularly sustained or intrathecal exposure—impacts the hypotha- lamic-pituitary-adrenal axis (HPA). HPA dysfunction creates common endocrine abnormalities such as changes in energy and libido. However, more importantly, HPA dysfunction can contribute to the chronic pain phenotype and worsen pain outcomes.
Testosterone is the most commonly considered affected hormone. In both humans and animals, chronic opioid administration decreases gonadotropin-releasing hormone (GnRH) from the hypothalamus—perhaps by inhibiting biosynthesis.38 Luteinizing hormone (LH) secretion from the pituitary decreases. Opioids directly inhibit LH release from the pituitary as well. FSH impact is limited. Testosterone, estradiol, and progesterone secretion are inhibited. This can lead to menstrual irregularities in women.39 Hypogonadism was noted in 86% of men receiving intrathecal opiates while the rate for sustained release oral opioids was 89%.40,41 Interestingly, this was not seen in those treated with buprenorphine.42
Symptoms associated with lower sex hormone levels are frequently seen in the chronic pain population. Sex hormones play an important role in analgesia.43 In a large population study, independent of age, body mass index, health and lifestyle factors, and osteoarthritis, women with andro- stenedione or estradiol levels in the lowest tertile had more chronic pain. In men with chronic pain, estradiol levels were also lower. The lowest tertile of 17-hydroxyprogesterone in women was associated with 38% more new onset pain.44 Under stressful states, salivary testosterone levels fall (while salivary cortisol levels increase), pain ratings increase, and pain thresholds decrease.45
It is not surprising that the osteoporotic compression fracture rate is 1.5-6 times higher with opioid use 46 This further complicates the questions regarding the correlation between epidural steroid injections and osteoporotic compression fractures.47 Sexual dysfunction is noted in multiple studies.39 Decreased sexual behavior may be due to the direct action of opioids on p and 6 receptors in the hypothalamus.38
DHEA levels are correlated with the pain experience. Higher DHEA-S is correlated with elevated pain thresholds and higher pain tolerances in post-menopausal woman.48 There seems to be an influence of decreased levels of DHEA-S and increased pain sensitivity in post-menopausal women with fibromyalgia syndrome.48 DHEA levels have been shown to be depressed in opioid users in a dose-dependent fashion, while adrenocorticotropic hormone (ACTH) levels remained normal.49
Changes in glucocorticoid activity are noted in the chronic pain state and have been noted in several chronic conditions—such as fibromyalgia, chronic fatigue, chronic pelvic pain, and temporomandibular joint disorder.50 Morning cortisol levels should register the highest of the day. Blunted awakening cortisol response is predictive of pain and fatigue.51 Patients with lumbar disc herniations with lower morning cortisol levels had lower physical function, perceived lower possibility of influencing their pain, and were more prone to catastrophize.52 Not all painful states decrease morning cortisol. To the contrary, in women with chronic widespread pain, morning cortisol was elevated.53
Nerve injury increases spinal glucocorticoid receptors.54 There is evidence that increased corticosterone combined with nerve injury may worsen allodynia. Transient dorsal horn microglia activation is noted with corticosterone. More importantly, increased activation of dorsal horn extracellular signal-regulated kinase phosphorylation (pERK) likely influences NMDA receptors to create allodynia through central sensitization.54
Unfortunately, chronic opioid exposure may decrease glucocorticoid response to ACTH, but lead to chronically elevated glucocorticoid levels.39 It is interesting to note that opioids impact the circadian rhythm of the HPA axis. Constant plasma levels of р-endorphin, ACTH, and cortisol were seen throughout the day rather than typical circadian variations.55 An opioid-induced elevation of glucocorticoid levels further exacerbates a dysfunctional glucocorticoid system.
The impact of opioids on thyroid function does not appear to be significant. Opioids can stimulate thyroid-stimulating hormone (TSH) via the hypothalamus—primarily through к-receptors.39 In a hypothyroid patient, there may be implications.38
Acute opioid administration results in an increase in growth hormone (GH) secretion.39 The chronic administration of intrathecal opioids is more complex. Chronic intrathecal administration of opioids has been associated with GH deficiency in a small number of patients (15%).40
